Quinazoline analogs as receptor tyrosine kinase inhibitors

ABSTRACT

This invention provides quinazoline analogs of Formula I:  
                 
 
where A is bonded to at least one of the carbons at the 5, 6, 7 or 8 position of the bicyclic ring, and the ring is substituted by up to two independent R 3  groups. The invention also includes methods of using compounds of Formula I as type I receptor tyrosine kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-in-Part application of U.S. patentapplication Ser. No. 10/642,440, filed Aug. 14, 2003, and claimspriority to U.S. Provisional Application No. 60/551,718, filed Mar. 10,2004, each of which is specifically incorporated herein by reference inits entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel inhibitors of type I receptor tyrosinekinases and related kinases, pharmaceutical compositions containing theinhibitors, and methods for preparing these inhibitors. The inhibitorsare useful for the treatment of hyperproliferative diseases, such ascancer and inflammation, in mammals and especially in humans.

2. Description of the State of the Art

The type I receptor tyrosine kinase family consists of four closelyrelated receptors: EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER), andErbB4 (HER4) (Reviewed in Riese and Stern, Bioessays (1998) 20:41-48,Olayioye et al., EMBO Journal (2000) 19:3159-3167 and Schlessinger, Cell(2002) 110:669-672). These are single pass transmembrane glycoproteinreceptors containing an extracellular ligand binding region and anintracellular signaling domain. In addition, all receptors contain anintracellular active tyrosine kinase domain with the exception of ErbB3whose kinase domain does not exhibit enzymatic activity. These receptorstransmit extracellular signals through the cytosol to the nucleus uponactivation. The activation process is initiated by ligand binding to theextacellular domain of the receptor by one of a number of differenthormones. Upon ligand binding, homo- or heterodimerization is inducedwhich results in the activation of the tyrosine kinase domains andphosphorylation of tyrosines on the intracellular signaling domains.Since no known ligand for ErbB2 has been described and ErbB3 lacks anactive kinase domain, these receptors must heterodimerize to elicit aresponse. The phosphotyrosines then recruit the necessary cofactors toinitiate several different signaling cascades including theras/raf/MEK/MAPK and PI3K/AKT pathways. The precise signal elicited willdepend on what ligands are present since the intracellular signalingdomains differ as to what pathways are activated. These signalingpathways lead to both cell proliferation and cell survival throughinhibition of apoptosis.

Several investigators have demonstrated the role of EGFR and ErbB2 indevelopment and cancer (Reviewed in Salomon, et al., Crit. Rev. Oncol.Hematol. (1995) 19:183-232, Klapper, et al., Adv. Cancer Res. (2000) 77,25-79 and Hynes and Stern, Biochim. Biophys. Acta (1994) 1198:165-184).Squamous carcinomas of the head and neck, and lung express high levelsof EGFR. Also, constitutively active EGFR has been found in gliomas,breast cancer and lung cancer. ErbB2 overexpression occurs inapproximately 30% of all breast cancer. It has also been implicated inother human cancers including colon, ovary, bladder, stomach, esophagus,lung, uterus and prostate. ErbB2 overexpression has also been correlatedwith poor prognosis in human cancer, including metastasis, and earlyrelapse.

The type I tyrosine kinase receptor family have been an active area ofanti-cancer research (Reviewed in Mendelsohn and Baselga, Oncogene(2000) 19:6550-6565 and Normanno et al., Endocrine-Related Cancer (2003)10:1-21). Several inhibitors of the EGFR and the ErbB2 signaling pathwayhave demonstrated clinical efficacy in cancer treatment. Herceptin, ahumanized version of anti-ErbB2 monoclonal antibody, was approved foruse in breast cancer in the United States in 1998. Iressa and Tarcevaare small molecule inhibitors of EGFR that are expected to becommercially available. In addition, several other antibodies and smallmolecules that target the interruption of the type I tyrosine kinasereceptor signaling pathways are in clinical and preclinical development.For example, IMC-225, which is a humanized antibody against theextracellular domain of EGFR demonstrated efficacy and will likely beapproved.

SUMMARY OF THE INVENTION

This invention provides compounds, methods to produce these compounds,and pharmaceutical compositions containing the compounds that inhibittype I receptor tyrosine kinases. Such compounds, generally referred toas quinazoline analogs, have utility as therapeutic agents for diseasesthat can be treated by the inhibition of type I receptor tyrosinekinases. They may also act as inhibitors of serine, threonine, and dualspecificity kinases inhibitors. In general, the invention relates toquinazoline derivatives of general Formula I:

-   -   wherein A is bonded to at least one of the carbons at positions        5, 6, 7 or 8 of the bicyclic ring and wherein the bicyclic ring        is substituted by zero, one or two independent R³ groups;    -   X is N, CH, CF or C—CN;    -   A is Q or Z;    -   R¹ is a substituted or unsubstituted, monocyclic or bicyclic,        aryl or heteroaryl moiety;    -   R² is H or a substituted or unsubstituted C₁₋₈ alkyl, allyl,        substituted benzyl;    -   R³ is hydrogen, halogen, cyano, nitro, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,        heterocyclyl, partially unsaturated heterocylyl,        heterocyclylalkyl, —NR⁴SO₂R⁵ —SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶,        —OC(O)R⁶, —NR⁴C(O)OR⁵, —NR⁴C(O)R⁶, —C(O)NR⁴R⁶, —NR⁴R⁶,        —NR⁴C(O)NR⁴R¹, —OR⁶, —S(O)R⁵, —SO₂R⁵, or SR⁶, wherein said        alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, partially        unsaturated heterocylyl, and heterocyclylalkyl is optionally        substituted with one to five groups independently selected from        the group consisting of oxo, halogen, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, —NR⁴SO₂R⁵, —SO₂NR⁶R⁴, —C(O)R⁶,        —C(O)OR⁶, —OC(O)R⁶, —NR⁴C(O)OR⁵, —NR⁴C(O)CR⁶, —C(O)NR⁴R⁶,        —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶, —NR⁴C(NCN)NR⁴R⁶, —OR⁶, —S(O)R⁵, —SO₂R⁵,        aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and        heterocyclylalkyl;    -   R¹⁰ is hydrogen, halogen, cyano, nitro, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,        heterocyclyl, heterocyclylalkyl, partially unsaturated        heterocyclyl —NR⁴SO₂R⁵ —SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶,        —NR⁴C(O)OR⁵, —NR⁴C(O)R⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶,        —OR⁶, —S(O)R⁵, —SO₂R⁵, or SR⁶, wherein said alkyl, alkenyl,        alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or        partially unsaturated heterocyclyl is optionally substituted        with one to five groups independently selected from the group        consisting of oxo, halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀        alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano,        nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,        azido, —NR⁴SO₂R⁵, —SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶,        —NR⁴C(O)OR⁵, —NR⁴C(O)CR⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶,        —NR⁴C(NCN)NR⁴R⁶, —OR⁶, —S(O)R⁵, —SO₂R⁵, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, heterocyclyl, and        heterocyclylalkyl, wherein g is 1 to 3 and each R¹⁰ can be the        same or different;    -   or one or more of said R¹⁰ groups may be independently joined        together with the atoms to which they are attached to complete a        3 to 10 membered cycloalkyl ring or heterocycloalkyl ring        optionally containing one or more additional heteroatoms        selected from the group consisting of O, S, SO, SO₂ and NR⁶,        where each ring carbon is optionally substituted with one to        three groups independently selected from the group consisting of        halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀        cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano, nitro,        trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,        OR⁸, NR⁶R, SR⁶, heteroaryl, arylalkyl, heteroarylalkyl,        heterocyclyl, and heterocyclylalkyl, provided said ring does not        contain two adjacent O or two adjacent S atoms;    -   wherein when R⁶═H then Z further includes    -   and wherein Z includes one or more R⁸ or R⁹ groups, wherein said        R⁸ and R⁹ groups may be bonded to the same or different atoms;    -   W and V are independently selected from the group consisting of        CR⁷R⁸, CR⁸R⁹, O, NR⁶, S, SO, and SO₂;    -   Y is selected from the group consisting of S, SO, SO₂, CR⁷CR⁸,        and CR⁸R⁹, provided that    -   when W is O, NR⁶, S, SO, or SO₂, then V is CR⁸R⁹, and    -   when V is O, NR⁶, S, SO, or SO₂, then W and Y are each CR⁸R⁹;    -   R⁴ is H or C₁₋₆ alkyl;    -   R⁵ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,        heterocyclylalkyl, or partially unsaturated heterocycle, wherein        said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl, and heterocyclylalkyl is optionally substituted        with one to five groups independently selected from the group        consisting of oxo, halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀        alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano,        nitro, OR⁶, NR⁴R⁶, SR⁶, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;    -   R⁶, R⁸ and R⁹ are independently selected from the group        consisting of hydrogen, trifluoromethyl, C₁-C₁₀ alkyl,        (CH₂)₀₋₄C₃-C₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl, wherein said alkyl,        cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, partially        unsaturated heterocyclyl, and heterocyclylalkyl is optionally        substituted with one to five groups independently selected from        the group consisting of oxo, halogen, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, cyano, nitro, OR⁶, NR⁶R⁸, SR⁶, trifluoromethyl,        difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl;    -   R⁷ is hydrogen, halogen, cyano, nitro, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,        heterocyclyl, heterocyclylalkyl, partially unsaturated        heterocycle, —NR⁴SO₂R⁵—SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶,        —NR⁴C(O)OR⁵, —NR⁴C(O)R⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶,        —OR⁶, —S(O)R⁵, —SO₂R⁵, or SR⁶, wherein said alkyl, alkenyl,        alkynyl, cycloalkyl, aryl, heteroaryl heterocyclyl, and        partially unsaturated heterocyclyl is optionally substituted        with one to five groups independently selected from the group        consisting of oxo, halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀        alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano,        nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,        azido, —NR⁴SO₂R⁵, —SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶,        —NR⁴C(O)OR⁵, —NR⁴C(O)CR⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶,        —NR⁴C(NCN)NR⁴R⁶, —OR⁶, —S(O)R⁵, —SO₂R⁵, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl;    -   or R⁴ and R⁶ together with the atoms to which they are attached        may be independently joined to complete a 3 to 10 membered        cycloalkyl ring or heterocycloalkyl ring optionally containing        one or more additional heteroatoms selected from the group        consisting of O, S, SO, SO₂ and NR⁶, wherein each ring carbon is        optionally substituted with one to three groups independently        selected from the group consisting of halogen, C₁-C₁₀ alkyl,        C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl, provided said ring does not        contain two adjacent O or two adjacent S atoms;    -   or R⁶ and R⁸ together with the atoms to which they are attached        may be independently joined to complete a 3 to 10 membered        cycloalkyl ring or heterocycloalkyl ring optionally containing        one or more additional heteroatoms selected from the group        consisting of O, S, SO, SO₂ and NR⁶, wherein each ring carbon is        optionally substituted with one to three groups independently        selected from the group consisting of halogen, C₁-C₁₀ alkyl,        C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl, provided said ring does not        contain two adjacent O or two adjacent S atoms;    -   or R⁷ and R⁸ together with the atoms to which they are attached        may be independently joined to complete a 3 to 10 membered        cycloalkyl ring or heterocycloalkyl ring optionally containing        one or more additional heteroatoms selected from the group        consisting of O, S, SO, SO₂ and NR⁶, wherein each ring carbon is        optionally substituted with one to three groups independently        selected from the group consisting of halogen, C₁-C₁₀ alkyl,        C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl; provided said ring does not        contain two adjacent O or two adjacent S atoms;    -   or R⁸ and R⁹ together with the atoms to which they are attached        may be independently joined to complete a 3 to 10 membered        cycloalkyl ring or heterocycloalkyl ring optionally containing        one or more additional heteroatoms selected from the group        consisting of O, S, SO, SO₂ and NR⁶, wherein each ring carbon        may be optionally substituted with one to three groups        independently selected from the group consisting of halogen,        C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl,        C₃-C₁₀ cycloalkylalkyl, cyano, nitro, trifluoromethyl,        difluoromethoxy, trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶,        heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially        unsaturated heterocyclyl and heterocyclylalkyl, provided said        ring does not contain two adjacent O or two adjacent S atoms;    -   or R⁶ and R¹⁰ together with the atoms to which they are attached        may be independently joined to complete a 3 to 10 membered        cycloalkyl ring or heterocycloalkyl ring optionally containing        one or more additional heteroatoms selected from the group        consisting of O, S, SO, SO₂ and NR⁶, wherein each ring carbon        may be optionally substituted with one to three groups        independently selected from the group consisting of halogen,        C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl,        C₃-C₁₀ cycloalkylalkyl, cyano, nitro, trifluoromethyl,        difluoromethoxy, trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶,        heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially        unsaturated heterocyclyl and heterocyclylalkyl, provided said        ring does not contain two adjacent O or two adjacent S atoms;    -   or R⁸ and R¹⁰ together with the atoms to which they are attached        may be independently joined to complete a 3 to 10 membered        cycloalkyl ring or heterocycloalkyl ring optionally containing        one or more additional heteroatoms selected from the group        consisting of O, S, SO, SO₂ and NR⁶, wherein each ring carbon        may be optionally substituted with one to three groups        independently selected from halogen, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl, provided said ring does not        contain two adjacent O or two adjacent S atoms.

The invention may also be directed to pharmaceutically acceptableprodrugs, pharmaceutically active metabolites, and pharmaceuticallyacceptable salts of the compound of general Formula I. Methods of makingthe compounds of Formula I are also described.

In a further aspect, the present invention provides compounds thatinhibit the activity of type I receptor tyrosine kinases such as EGFR,ErbB2, ErbB3, ErbB4, VEGFR², Flt3 and FGFR, comprising compounds ofFormula I.

In a further aspect, the present invention provides a method of treatingdiseases or medical conditions mediated by type I receptor tyrosinekinases which comprises administering to a warm-blooded animal aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt or in vivo cleavable prodrug thereof.

In a further aspect, the present invention provides a method ofinhibiting the production of type I receptor kinases which comprisesadministering to a warm-blooded animal an effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt or in vivo cleavableprodrug thereof.

In a further aspect, the present invention provides a method ofproviding type I receptor kinase inhibitory effect comprisingadministering to a warm-blooded animal an effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt or in vivo cleavableprodrug thereof.

In a further aspect, the present invention provides treating orpreventing a type I receptor kinase mediated condition, comprisingadministering an amount of a compound effective to treat or prevent saidtype I receptor kinase-mediated condition or a pharmaceuticalcomposition comprising said compound, to a human or animal in needthereof, wherein said compound is a compound of Formula I, or apharmaceutically-acceptable salt or in vivo cleavable prodrug thereof.The type I receptor kinase mediated condition that can be treatedaccording to the methods of this invention includes hyperproliferativedisorders, such as cancer of the head and neck, lung, breast, colon,ovary, bladder, stomach, kidney, skin, pancreas, leukemias, lymphomas,esophagus, uterus or prostate, among other kinds of hyperproliferativedisorders.

The compounds of Formula I may be used advantageously in combinationwith other known therapeutic agents.

The invention also relates to pharmaceutical compositions comprising aneffective amount of an agent selected from compounds of Formula I or apharmaceutically acceptable prodrug, pharmaceutically active metabolite,or pharmaceutically acceptable salt thereof.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification, or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated herein and form a partof the specification, illustrate non-limiting embodiments of the presentinvention, and together with the description, serve to explain theprinciples of the invention.

In the Figures:

FIG. 1 shows a reaction scheme for the preparation of imino amidines.

FIG. 2 shows another reaction scheme for the preparation of iminoamidines.

FIG. 3 shows another reaction scheme for the preparation of iminoamidines.

FIG. 4 shows another reaction scheme for the preparation of iminoamidines.

FIG. 5 shows a reaction scheme for the preparation of oxazolines.

FIG. 6 shows another reaction scheme for the preparation of oxazolines.

DETAILED DESCRIPTION OF THE INVENTION

The inventive compounds of Formula I are useful for inhibiting type Ireceptor tyrosine kinases, such as EGFR (HER1), ErbB2 (HER2), ErbB3(HER3), ErbB4 (HER4), VEGFR2, Flt3 and FGFR. The compounds of Formula Imay also be useful as inhibitors of serine, threonine, and dualspecificity kinases such as Raf, MEK, and p38. Such compounds haveutility as therapeutic agents for diseases that can be treated by theinhibition of the type I receptor tyrosine kinases signaling pathway andserine, threonine, and dual specificity kinase pathways. In general, theinvention relates to compounds of the general Formula I:

-   -   wherein A is bonded to at least one of the carbons at positions        5, 6, 7 or 8 of the bicyclic ring and wherein the bicyclic ring        is substituted by zero, one or two independent R³ groups;    -   X is N, CH, CF or C—CN;    -   A is Q or Z;    -   R¹ is a substituted or unsubstituted, monocyclic or bicyclic,        aryl or heteroaryl moiety;    -   R² is H or a substituted or unsubstituted C₁₋₈ alkyl;    -   R³ is hydrogen, halogen, cyano, nitro, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,        heterocyclyl, partially unsaturated heterocylyl,        heterocyclylalkyl, —NR⁴SO₂R⁵—SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶,        —OC(O)R⁶, —NR⁴C(O)OR⁵, —NR⁴C(O)R⁶, —C(O)NR⁴R⁶, —NR⁴R⁶,        —NR⁴C(O)NR⁴R⁶, —OR⁶, —S(O)R⁵, —SO₂R⁵, or SR⁶, wherein said        alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, partially        unsaturated heterocylyl, and heterocyclylalkyl is optionally        substituted with one to five groups independently selected from        the group consisting of oxo, halogen, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, —NR⁴SO₂R⁵, —SO₂NR⁶R⁴, —C(O)R⁶,        —C(O)OR⁶, —OC(O)R⁶, —NR⁴C(O)OR⁵, —NR⁴C(O)CR⁶, —C(O)NR⁴R⁶,        —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶, —NR⁴C(NCN)NR⁴R⁶, —OR⁶, —S(O)R⁵, —SO₂R⁵,        aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and        heterocyclylalkyl;    -   R¹⁰ is hydrogen, halogen, cyano, nitro, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,        heterocyclyl, heterocyclylalkyl, partially unsaturated        heterocyclyl —NR⁴SO₂R⁵—SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶,        —NR⁴C(O)OR⁵, —NR⁴C(O)R⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶,        —OR⁶, —S(O)R⁵, —SO₂R⁵, or SR⁶, wherein said alkyl, alkenyl,        alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or        partially unsaturated heterocyclyl is optionally substituted        with one to five groups independently selected from the group        consisting of oxo, halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀        alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano,        nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,        azido, —NR⁴SO₂R⁵, —SO₂NR⁴R⁴, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶,        —NR⁴C(O)OR⁵, —NR⁴C(O)CR⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶,        —NR⁴C(NCN)NR⁴R⁶, —OR⁶, —S(O)R⁵, —SO₂R⁵, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, heterocyclyl, and        heterocyclylalkyl, wherein g is 1 to 3 and each R¹⁰ can be the        same or different;    -   or one or more of said R¹⁰ groups may be independently joined        together with the atoms to which they are attached to complete a        3 to 10 membered cycloalkyl ring or heterocycloalkyl ring        optionally containing one or more additional heteroatoms        selected from the group consisting of O, S, SO, SO₂ and NR⁶,        where each ring carbon is optionally substituted with one to        three groups independently selected from the group consisting of        halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀        cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano, nitro,        trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl,        OR⁸, NR⁶R⁸, SR⁶, heteroaryl, arylalkyl, heteroarylalkyl,        heterocyclyl, and heterocyclylalkyl, provided said ring does not        contain two adjacent O or two adjacent S atoms;    -   wherein when R⁶═H then Z further includes    -   and wherein Z includes one or more R⁸ or R⁹ groups, wherein said        R⁸ and R⁹ groups may be bonded to the same or different atoms;    -   W and V are independently selected from the group consisting of        CR⁷R⁸, CR⁸R⁹, O, NR⁶, S, SO, and SO₂, and Y is selected from the        group consisting of S, SO, SO₂, CR⁷CR⁸, and CR⁸R⁹, provided that    -   when W is O, NR⁶, S, SO, or SO₂, then V is CR⁸R⁹, and    -   when V is O, NR⁶, S, SO, or SO₂, then W and Y are each CR⁸R⁹;    -   R⁴ is H or C₁₋₆ alkyl;    -   R⁵ is trifluoromethyl, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,        heterocyclylalkyl, or partially unsaturated heterocycle, wherein        said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl, and heterocyclylalkyl is optionally substituted        with one to five groups independently selected from the group        consisting of oxo, halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀        alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano,        nitro, OR⁶, NR⁴R⁶, SR⁶, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl,        heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;    -   R⁶, R⁸ and R⁹ are independently selected from the group        consisting of hydrogen, trifluoromethyl, C₁-C₁₀ alkyl,        (CH₂)₀₋₄C₃-C₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl, wherein said alkyl,        cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, partially        unsaturated heterocyclyl, and heterocyclylalkyl is optionally        substituted with one to five groups independently selected from        the group consisting of oxo, halogen, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, cyano, nitro, OR⁶, NR⁶R⁸, SR⁶, trifluoromethyl,        difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl;    -   R⁷ is hydrogen, halogen, cyano, nitro, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,        heterocyclyl, heterocyclylalkyl, partially unsaturated        heterocycle, —NR⁴SO₂R⁵ —SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶,        —NR⁴C(O)OR⁵, —NR⁴C(O)R⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶,        —OR⁶, —S(O)R⁵, —SO₂R⁵, or SR⁶, wherein said alkyl, alkenyl,        alkynyl, cycloalkyl, aryl, heteroaryl heterocyclyl, and        partially unsaturated heterocyclyl is optionally substituted        with one to five groups independently selected from the group        consisting of oxo, halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀        alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano,        nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy,        azido, —NR⁴SO₂R⁵, —SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶,        —NR⁴C(O)OR⁵, —NR⁴C(O)CR⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶,        —NR⁴C(NCN)NR⁴R⁶, —OR⁶, —S(O)R⁵, —SO₂R⁵, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl;    -   or R⁴ and R⁶ together with the atoms to which they are attached        may be independently joined to complete a 3 to 10 membered        cycloalkyl ring or heterocycloalkyl ring optionally containing        one or more additional heteroatoms selected from the group        consisting of O, S, SO, SO₂ and NR⁶, wherein each ring carbon is        optionally substituted with one to three groups independently        selected from the group consisting of halogen, C₁-C₁₀ alkyl,        C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl, provided said ring does not        contain two adjacent O or two adjacent S atoms;    -   or R⁶ and R⁸ together with the atoms to which they are attached        may be independently joined to complete a 3 to 10 membered        cycloalkyl ring or heterocycloalkyl ring optionally containing        one or more additional heteroatoms selected from the group        consisting of O, S, SO, SO₂ and NR⁶, wherein each ring carbon is        optionally substituted with one to three groups independently        selected from the group consisting of halogen, C₁-C₁₀ alkyl,        C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl, provided said ring does not        contain two adjacent O or two adjacent S atoms;    -   or R⁷ and R⁸ together with the atoms to which they are attached        may be independently joined to complete a 3 to 10 membered        cycloalkyl ring or heterocycloalkyl ring optionally containing        one or more additional heteroatoms selected from the group        consisting of O, S, SO, SO₂ and NR⁶, wherein each ring carbon is        optionally substituted with one to three groups independently        selected from the group consisting of halogen, C₁-C₁₀ alkyl,        C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl; provided said ring does not        contain two adjacent O or two adjacent S atoms;    -   or R⁸ and R⁹ together with the atoms to which they are attached        may be independently joined to complete a 3 to 10 membered        cycloalkyl ring or heterocycloalkyl ring optionally containing        one or more additional heteroatoms selected from the group        consisting of O, S, SO, SO₂ and NR⁶, wherein each ring carbon        may be optionally substituted with one to three groups        independently selected from the group consisting of halogen,        C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl,        C₃-C₁₀ cycloalkylalkyl, cyano, nitro, trifluoromethyl,        difluoromethoxy, trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶,        heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially        unsaturated heterocyclyl and heterocyclylalkyl, provided said        ring does not contain two adjacent O or two adjacent S atoms;    -   or R⁶ and R¹⁰ together with the atoms to which they are attached        may be independently joined to complete a 3 to 10 membered        cycloalkyl ring or heterocycloalkyl ring optionally containing        one or more additional heteroatoms selected from the group        consisting of O, S, SO, SO₂ and NR⁶, wherein each ring carbon        may be optionally substituted with one to three groups        independently selected from the group consisting of halogen,        C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl,        C₃-C₁₀ cycloalkylalkyl, cyano, nitro, trifluoromethyl,        difluoromethoxy, trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶,        heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially        unsaturated heterocyclyl and heterocyclylalkyl, provided said        ring does not contain two adjacent O or two adjacent S atoms;    -   or R⁸ and R¹⁰ together with the atoms to which they are attached        may be independently joined to complete a 3 to 10 membered        cycloalkyl ring or heterocycloalkyl ring optionally containing        one or more additional heteroatoms selected from the group        consisting of O, S, SO, SO₂ and NR⁶, wherein each ring carbon        may be optionally substituted with one to three groups        independently selected from halogen, C₁-C₁₀ alkyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀        cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶, heteroaryl,        arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated        heterocyclyl and heterocyclylalkyl, provided said ring does not        contain two adjacent O or two adjacent S atoms.

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms, wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. Examples ofalkyl groups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,tert-pentyl, hexyl, isohexyl, and the like.

“Alkylene” means a linear or branched saturated divalent hydrocarbonradical of one to twelve carbon atoms, e.g., methylene, ethylene,propylene, 2-methylpropylene, pentylene, and the like.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to twelve carbon atoms, containing at leastone double bond, e.g., ethenyl, propenyl, and the like, wherein thealkenyl radical may be optionally substituted independently with one ormore substituents described herein, and includes radicals having “cis”and “trans” orientations, or alternatively, “E” and “Z” orientations.

The term “alkenylene” refers to a linear or branched divalenthydrocarbon radical of two to twelve carbons containing at least onedouble bond, wherein the alkenylene radical may be optionallysubstituted independently with one or more substituents describedherein. Examples include, but are not limited to, ethenylene,propenylene, and the like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to twelve carbon atoms containing at least one triplebond. Examples include, but are not limited to, ethynyl, propynyl, andthe like, wherein the alkynyl radical may be optionally substitutedindependently with one or more substituents described herein.

The term “alkynylene” to a linear or branched divalent hydrocarbonradical of two to twelve carbons containing at least one triple bond,wherein the alkynylene radical may be optionally substitutedindependently with one or more substituents described herein.

The term “allyl” refers to a radical having the formula RC═CHCHR,wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, or any substituent as defined herein, wherein theallyl may be optionally substituted independently with one or moresubstituents described herein.

The term “cycloalkyl” refers to saturated or partially unsaturatedcyclic hydrocarbon radical having from three to twelve carbon atoms,wherein the cycloalkyl may be optionally substituted independently withone or more substituents described herein. The term “cycloalkyl” furtherincludes bicyclic and tricyclic cycloalkyl structures, wherein thebicyclic and tricyclic structures may include a saturated or partiallyunsaturated cycloalkyl fused to a saturated or partially unsaturatedcycloalkyl or heterocycloalkyl ring or an aryl or heteroaryl ring.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantly, norboranes and the like.

The term “heteroalkyl” refers to saturated linear or branched-chainmonovalent hydrocarbon radical of one to twelve carbon atoms, wherein atleast one of the carbon atoms is replaced with a heteroatom selectedfrom N, O, or S, and wherein the radical may be a carbon radical orheteroatom radical (i.e., the heteroatom may appear in the middle or atthe end of the radical). The heteroalkyl radical may be optionallysubstituted independently with one or more substituents describedherein. The term “heteroalkyl” encompasses alkoxy and heteroalkoxyradicals.

The term “heterocycloalkyl” refers to a saturated or partiallyunsaturated cyclic radical of 3 to 8 ring atoms in which at least onering atom is a heteroatom selected from nitrogen, oxygen and sulfur, theremaining ring atoms being C where one or more ring atoms may beoptionally substituted independently with one or more substituentdescribed below. The radical may be a carbon radical or heteroatomradical. “Heterocycloalkyl” also includes radicals where heterocycleradicals are fused with aromatic or heteroaromatic rings. Examples ofheterocycloalkyl rings include, but are not limited to, pyrrolidine,piperidine, piperazine, tetrahydropyranyl, morpholine, thiomorpholine,homopiperazine, phthalimide, and derivatives thereof.

The term “heteroalkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of three to twelve carbon atoms, containing at leastone double bond, e.g., ethenyl, propenyl, and the like, wherein at leastone of the carbon atoms is replaced with a heteroatom selected from N,O, or S, and wherein the radical may be a carbon radical or heteroatomradical (i.e., the heteroatom may appear in the middle or at the end ofthe radical). The heteroalkenyl radical may be optionally substitutedindependently with one or more substituents described herein, andincludes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations.

The term “heteroalkynyl” refers to a linear or branched monovalenthydrocarbon radical of three to twelve carbon atoms containing at leastone triple bond. Examples include, but are not limited to, ethynyl,propynyl, and the like, wherein at least one of the carbon atoms isreplaced with a heteroatom selected from N, O, or S, and wherein theradical may be a carbon radical or heteroatom radical (i.e., theheteroatom may appear in the middle or at the end of the radical). Theheteroalkynyl radical may be optionally substituted independently withone or more substituents described herein.

The term “heteroallyl” refers to radicals having the formula RC═CHCHR,wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, or any substituent as defined herein, wherein at leastone of the carbon atoms is replaced with a heteroatom selected from N,O, or S, and wherein the radical may be a carbon radical or heteroatomradical (i.e., the heteroatom may appear in the middle or at the end ofthe radical). The heteroallyl may be optionally substitutedindependently with one or more substituents described herein.

“Aryl” means a monovalent aromatic hydrocarbon monocyclic radical of 6to 10 ring atoms or a polycyclic aromatic hydrocarbon, optionallysubstituted independently with one or more substituents describedherein. More specifically the term aryl includes, but is not limited to,phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.

“Heteroaryl” means a monovalent monocyclic aromatic radical of 5 to 10ring atoms or a polycyclic aromatic radical, containing one or more ringheteroatoms selected from N, O, or S, the remaining ring atoms being C.The aromatic radical is optionally substituted independently with one ormore substituents described herein. Examples include, but are notlimited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl,imidazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl,thiazolyl, and derivatives thereof.

The term “halo” represents fluoro, chloro, bromo or iodo. Likewise, theterm “halogen” refers to a fluorine, chlorine, bromine, or iodinesubstituent.

In general, the various moieties or functional groups of the compoundsof Formula I may be optionally substituted by one or more substituents.Examples of substituents suitable for purposes of this inventioninclude, but are not limited to, halo, alkyl, allyl, alkenyl, alkynyl,heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy,heteroalkoxy, G_(n)-cycloalkyl, G_(n)-heterocycloalkyl, G_(n)—OR,G_(n)—NO₂, G_(n)—CN, G_(n)—CO₂R, G_(n)—(C═O)R, G_(n)—O(C═O)R,G_(n)—O-alkyl, G_(n)—OAr, G_(n)—SH, G_(n)—SR, G_(n)—SOR, G_(n)—SO₂R,G_(n)—S—Ar, G_(n)—SOAr, G_(n)—O₂Ar, aryl, heteroaryl, G_(n)—Ar,G_(n)—(C═O)NR²R³, G_(n)—NR²R³, G_(n)—NR(C═O)R, G_(n)—SO₂NR²R³, PO₃H₂,and SO₃H₂, wherein G is alkylene having from 1 to 4 carbons, oralkenylene or alkynylene each having from 2 to 4 carbons, wherein saidalkylene, alkenylene, or alkynylene may be substituted or unsubstituted;n is zero or 1; R¹, R², and R³ are independently alkyl, allyl, alkenyl,alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy,heteroalkoxy, G_(n)-cycloalkyl, or G_(n)-heterocycloalkyl; and Ar isaryl or heteroaryl, wherein said alkyl, allyl, alkenyl, alkynyl,heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy,heteroalkoxy, G_(n)-cycloalkyl, G_(n)-heterocycloalkyl, Ar, R¹, R², andR³ may be further substituted or unsubstituted.

The compounds of this invention may possess one or more asymmetriccenters, and such compounds can be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. Accordingly, this inventionalso includes racemates and resolved enantiomers, and diastereomerscompounds of the Formula I. The methods for the determination ofstereochemistry and the separation of stereoisomers are well known inthe art (see discussion in Chapter 4 of “Advanced Organic Chemistry”,4th edition J. March, John Wiley and Sons, New York, 1992).

In addition to compounds of the Formula I, the invention also includessolvates, pharmaceutically acceptable prodrugs, pharmaceutically activemetabolites, and pharmaceutically acceptable salts of such compounds.

The term “solvate” refers to an aggregate of a molecule with one or moresolvent molecules.

A “pharmaceutically acceptable prodrug” is a compound that may beconverted under physiological conditions or by solvolysis to thespecified compound or to a pharmaceutically acceptable salt of suchcompound.

A “pharmaceutically active metabolite” is a pharmacologically activeproduct produced through metabolism in the body of a specified compoundor salt thereof. Metabolites of a compound may be identified usingroutine techniques known in the art and their activities determinedusing tests such as those described herein.

Prodrugs and active metabolites of a compound may be identified usingroutine techniques known in the art. Various forms of prodrugs are knownin the art. For examples of such prodrug derivatives, see, for example,a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5“Design andApplication of Prodrugs”, by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984).

A “pharmaceutically acceptable salt” is a salt that retains thebiological effectiveness of the free acids and bases of the specifiedcompound and that is not biologically or otherwise undesirable. Acompound of the invention may possess a sufficiently acidic, asufficiently basic, or both functional groups, and accordingly reactwith any of a number of inorganic or organic bases, and inorganic andorganic acids, to form a pharmaceutically acceptable sale. Examples ofpharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with a mineral ororganic acid or an inorganic base, such salts including sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyn-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitromenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, pheylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates,methanesulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, tosylates, besylates, acetate and mandelates.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as aceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, apyranosidyl acid such as glucuronic acid or galacturonic acid, analphahydroxy acid such as citric acid or tartaric acid, an amino acidsuch as aspartic acid or glutamic acid, an aromatic acid such as benzoicacid or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid orethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary or tertiary), an alkali metal hydroxide oralkaline earth metal hydroxide, or the like. Illustrative examples ofsuitable salts include, but are not limited to, organic salts derivedfrom amino acids, such as glycine and arginine, ammonia, primary,secondary, and tertiary amines, and cyclic amines, such as piperidine,morpholine and piperazine, and inorganic salts derived from sodium,calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminumand lithium.

The inventive compounds may be prepared using the reaction routes andsynthesis schemes as described below, employing the techniques availablein the art using starting materials that are readily available.

Therapeutic Aspects of the Invention

Therapeutically effective amounts of the compounds of the invention maybe used to treat diseases mediated by modulation or regulation of type Ireceptor tyrosine kinases and/or serine, threonine, and/or dualspecificity kinases. An “effective amount” is intended to mean thatamount of compound that, when administered to a mammal in need of suchtreatment, is sufficient to effect treatment for a disease mediated bythe activity of one or more type I receptor tyrosine kinases and/orserine, threonine, and/or dual specificity kinases. Thus, for example, atherapeutically effective amount of a compound selected from Formula Ior a salt, active metabolite or prodrug thereof, is a quantitysufficient to modulate, regulate, or inhibit the activity of one or moretype I receptor tyrosine kinases and/or serine, threonine, and/or dualspecificity kinases such that a disease condition which is mediated bythat activity is reduced or alleviated.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight) of the mammal inneed of treatment, but can nevertheless be routinely determined by oneskilled in the art. “Treating” is intended to mean at least themitigation of a disease condition in a mammal, such as a human, that isaffected, at least in part, by the activity of one or more type Ireceptor tyrosine kinases and/or serine, threonine, and/or dualspecificity kinases, and includes, but is not limited to, preventing thedisease condition from occurring in a mammal, particularly when themammal is found to be predisposed to having the disease condition buthas not yet been diagnosed as having it; modulating and/or inhibitingthe disease condition; and/or alleviating the disease condition.

In order to use a compound of the Formula I, or a pharmaceuticallyacceptable salt or in vivo cleavable prodrug thereof, for thetherapeutic treatment (including prophylactic treatment) of mammalsincluding humans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. According tothis aspect of the invention there is provided a pharmaceuticalcomposition that comprises a compound of the Formula I, or apharmaceutically acceptable salt or in vivo cleavable prodrug thereof,as defined hereinbefore in association with a pharmaceuticallyacceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, or intramusculardosing or as a suppository for rectal dosing). For example, compositionsintended for oral use may contain one or more coloring, sweetening,flavoring and/or preservative agents.

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),coloring agents, flavoring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspendingagent, and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients such as sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil such as liquid paraffin,or a mixture of any of these. Suitable emulsifying agents may be, forexample, naturally-occurring gums such as gum acacia or gum tragacanth,naturally-occurring phosphatides such as soya bean, lecithin, an estersor partial esters derived from fatty acids and hexitol anhydrides (forexample sorbitan monooleate) and condensation products of the saidpartial esters with ethylene oxide such as polyoxyethylene sorbitanmonooleate. The emulsions may also contain sweetening, flavoring andpreservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient, which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 μm or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurized aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulations, see Chapter 25.2 in Volume 5 ofComprehensive Medicinal Chemistry (Corwin Hansch; Chairman of EditorialBoard), Pergamon Press, 1990.

The amount of a compound of this invention that is combined with one ormore excipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans may contain, for example, from 0.5 mg to 2 g ofactive agent compounded with an appropriate and convenient amount ofexcipients, which may vary from about 5 to about 98 percent by weight ofthe total composition. Dosage unit forms will generally contain about 1mg to about 500 mg of an active ingredient. For further information onroutes of administration and dosage regimes, see Chapter 25.3 in Volume5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman ofEditorial Board), Pergamon Press, 1990.

The size of the dose for therapeutic or prophylactic purposes of acompound of Formula I will naturally vary according to the nature andseverity of the conditions, the age and sex of the animal or patient andthe route of administration, according to well known principles ofmedicine.

Although the compounds of Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to control type I receptortyrosine kinases and/or serine, threonine, and/or dual specificitykinases. Thus, they are useful as pharmacological standards for use inthe development of new biological tests and in the search for newpharmacological agents.

The activity of the compounds of this invention may be assayed for typeI receptor tyrosine kinases inhibition and/or serine, threonine, and/ordual specificity kinases in vitro, in vivo, or in a cell line. In vitroassays include assays that determine inhibition of the kinase activity.Alternate in vitro assays quantitate the ability of the inhibitor tobind to kinases and may be measured either by radiolabelling theinhibitor prior to binding, isolating the inhibitor/kinase complex anddetermining the amount of radiolabel bound, or by running a competitionexperiment where new inhibitors are incubated with known radioligands.These and other useful in vitro and cell culture assays are well knownto those of skill in the art.

Although the invention has been described and illustrated with a certaindegree of particularity, it is understood that the present disclosurehas been made only by way of example, and that numerous changes in thecombination and arrangement of parts can be resorted to by those skilledin the art without departing from the spirit and scope of the invention,as hereinafter claimed.

BIOLOGICAL EXAMPLES EGFR/ErbB2 Enzymatic Assays

Thermo LabSystems Immulon 4HBX 96-well plates are coated by incubationovernight at room temperature with 100 μL per well of 0.25 mg/mL Poly(Glu, Tyr) 4:1 (PGT) (Sigma Chemical Co., St. Louis, Mo.) in PBS(phosphate buffered saline). Excess PGT is removed by aspiration, andthe plate is washed three times with wash buffer (0.1% Tween 20 in PBS).The kinase reaction is performed in 100 μL of 50 mM HEPES (pH 7.3)containing 125 mM sodium chloride, 24 mM magnesium chloride, 0.1 mMsodium orthovanadate, 15 μM ATP (adenosine triphosphate) and 0.3units/mL EGFR (epidermal growth factor receptor) (BIOMOL ResearchLaboratories, Inc., Plymouth Meeting, Pa.). The compound in DMSO(dimethylsulfoxide) is added to give a final DMSO concentration of about1%. Phosporylation is initiated by the addition of ATP and incubated for30 minutes at room temperature. The kinase reaction is terminated byaspiration of the reaction mixture and subsequent washing with washbuffer (see above). Phosphorylated PGT is detected by 30 incubation with100 μL per well HRP conjugated PY20 antiphosphotyrosine antibody (ZymedLaboratories, Inc., South San Francisco, Calif.) diluted to 0.2 μg/mL in3% BSA and 0.05% Tween 20 in PBS. Antibody is removed by aspiration, andthe plate is washed with wash buffer. The colorimetric signal isdeveloped by the addition of 100 μL per well TMB Microwell PeroxidaseSubstrate (Kirkegaard and Perry, Gaithersburg, Md.), and stopped by theaddition of 100 μL per well 1M phosphoric acid. Phosphotyrosine inmeasured by absorbance at 450 nm.

The ErbB2 kinase is as above using 250 ng/mL erbB2 intracellular domainin place of EGFR. The intracellular domain of the ErbB2 tyrosine kinase(amino acids 691-1255) is expressed as a his-tagged protein inBaculovirus and purified by nickel chelating, ion exchange and sizeexclusion chromatography.

Compounds of the present invention have IC₅₀'s from less than 1 nM to 50mM.

PREPARATIVE EXAMPLES

An illustration of the preparation of compounds of the present inventionis shown in FIGS. 1-6.

FIG. 1 illustrates the synthesis of imino amidine compounds of thepresent invention. Hydrazones (3) can be prepared by standard methods ofcondensation of the aldehyde (1) with hydrazine (2). This can beaccomplished in a range of organic solvents. Preferably, thecondensation is performed in a mixed solvent system of DCM and IPA.Couplings to form imino amidines (5) can be achieved by heatinghydrazone (3) in a solvent mixture of THF and EPA at about 50° C. in thepresence of an imidate (4).

FIG. 2 illustrates an alternative synthesis of imino amidine compoundsof the present invention. In this route, an amide (6) is treated withPOCl3 in a suitable organic solvent like benzene or DCM to form theimidoyl chloride intermediate. Hydrazone (3) is then added to thismixture to generate the desired imino amidine (5). This coupling mayrequire slightly elevated temperatures (45 to 90° C.).

FIGS. 3 and 4 outline syntheses of imino amidine compounds of thepresent invention in which a imino amidine (7) is prepared and thencondensed with aldehyde (1). In FIG. 3, imino amidine (7) can beprepared by coupling of hydrazine (2) with imidate (4) in a suitableorganic solvent. The resulting imino amidine (7) can then be condensedwith aldehyde (1) in a suitable organic solvent such as THF and IPA orEtOH at room temperature or slightly elevated temperature (45 to 90° C.)to furnish the desired imino amidine (5). In FIG. 4, imino amidine (7)can be prepared by coupling hydrazine (2) with thioimidate (8) in asuitable organic solvent. As in FIG. 3, the resulting imino amidine (7)can then be condensed with aldehyde (1) in a suitable organic solventsuch as THF and IPA or EtOH at room temperature or slightly elevatedtemperature (45 to 90° C.) to furnish the desired imino amidine (5).

Oxazoline compounds of formula I can be prepared as outlined in FIG. 5.Aniline (9) can be condensed with thioCDI in a suitable organic solventsuch as a mixture of THF and DCE. The resulting intermediate is notisolated but rather treated in situ with amino alcohol (10). Theaddition reaction can be accomplished at room temperature or at slightlyelevated temperatures (45 to 90° C.). Generally, the resulting thiourea(11) can be isolated and carried forward without purification. Thedesired oxazoline (12) can be prepared from the thiourea (11) by one ofseveral routes outlined in FIG. 5. The thiourea (11) can be treated withtosyl chloride and NaOH in a mixture of THF and water at roomtemperature. Alternatively, the thiourea (11) can be treated with avariety of carbodiimidates such as in EDCI, DCC, DCI in suitable organicsolvents such as THF, DMF, DCM or DCE at room temperature or slightlyelevated temperatures (45 to 90° C.).

FIG. 6 illustrates an alternative approach to oxazoline compounds of thepresent invention. Aniline (9) can be coupled with diphenylN-cyanocarbonimidate (13) with or without a base such as NaH or Et₃N inorganic solvents such as DMF, MeCN, dioxane, pyridine, IPA or DCM atroom temperature or elevated temperatures (45 to 120° C.) to give cyanoisourea (14). Preferably, cyano isourea (14) is formed by couplinganiline (9) and diphenyl N-cyanocarbonimidate (13) in a mixture ofTHF/DCE/tBuOH at 80-90° C. Oxazoline (12) can be prepared by couplingamino alcohol (10) and cyano isourea (14) in a variety of organicsolvents including THF and IPA. Preferably, the coupling of (10) and(14) is accomplished in a mixture of THF and EPA at elevatedtemperatures (45 to 120° C.).

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other quinazoline analogs of the invention, and alternative methodsfor preparing the compounds of this invention are deemed to be withinthe scope of this invention. For example, the synthesis ofnon-exemplified compounds according to the invention may be successfullyperformed by modifications apparent to those skilled in the art, e.g.,by appropriately protecting interfering groups, by utilizing othersuitable reagents known in the art other than those described, and/or bymaking routine modifications of reaction conditions. Alternatively,other reactions disclosed herein or known in the art will be recognizedas having applicability for preparing other compounds of the invention.

EXAMPLES

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge, and were used without further purification unlessotherwise indicated.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SepPak cartridge(Waters).

¹H-NMR spectra were recorded on a Varian instrument operating at 400MHz. ¹H-NMR spectra were obtained as CDCl₃ solutions (reported in ppm),using chloroform as the reference standard (7.25 ppm). Other NMRsolvents were used as needed. When peak multiplicities are reported, thefollowing abbreviations are used: s (singlet), d (doublet), t (triplet),m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet oftriplets).

Example 1

Preparation of(E)-2-methoxy-N-((4-(3-methyl-4-phenoxyphenylamino)quinazolin-6-yl)methyleneamino)acetamidine

Step A:(6-Hydrazonomethylquinazolin-4-yl)-(3-methyl-4-phenoxyphenyl)amine isprepared by adding hydrazine (50 mg, 1.00 mmol) to a solution of4-(3-methyl-4-phenoxyphenylamino)-quinazoline-6-carbaldehyde (250 mg,0.70 mmol) in a 1:1 mixture of DCM:IPA (6 mL). After stirring at roomtemperature for 4 hours, excess hydrazine and solvent are removed underreduced pressure to give the desired hydrazone as a brown solid which iscarried forward without purification.

Step B:(E)-2-Methoxy-N-((4-(3-methyl-4-phenoxyphenylamino)quinazolin-6-yl)methyleneamino)acetamidineis prepared by adding(6-hydrazonomethylquinazolin-4-yl)-(3-methyl-4-phenoxyphenyl)amine (30mg, 0.081 mmol) to a stirred mixture of Et₃N (20 mg, 0.19 mmol) and2-methoxyacetimidic acid methyl ester (20 mg, 0.20 mmol) in a 1:1mixture of DCM:IPA (4 mL). After stirring the reaction mixture at 50° C.for 1 hour, it is cooled to room temperature and stirred for 16 hours.Concentration and purification by column chromatography (10:8:1EtOAc:Hexanes:MeOH) provides the desired product (16 mg, 45%). MS ESI(+) m/z 441 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.64 (s, 1H), 8.49(s, 1H), 8.41 (m, 2H), 7.76 (d, 1H), 7.63 (d, 1H), 7.55 (dd, 1H), 7.32(m, 2H), 7.05 (m, 1H), 6.93 (m, 3H), 4.13 (s, 2H), 3.45 (s, 3H), 3.41(s, 1H), 2.24 (s, 3H).

The following compounds (Examples 2-5) are prepared as described inExample 1 using the appropriate quinazoline-6-aldehyde, hydrazine andimidate.

Example 2

(E)-2-Methoxy-N-methyl-N-((4-(3-methyl-4-phenoxyphenylaminoquinazolin-6-yl)methyleneamino)acetamidine

MS APCI (+) m/z 455 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.48 (s,1H), 8.23 (s, 1H), 8.26 (d, 1H), 7.91 (s, 1H), 7.77 (d, 1H), 7.64 (d,1H), 7.54 (dd, 1H), 7.32 (m, 2H), 7.05 (m, 1H), 6.94 (m, 3H), 4.55 (s,2H), 3.72 (m, 1H), 3.54 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H).

Example 3

(E)-N-((4-(4-(3-Fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)methyleneamino)-2-methoxyacetamidine

MS APCI (+) m/z 493, 495 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 8.75 (s, 1H), 8.59 (s, 1H), 8.46 (d, 1H), 8.40 (s, 1H), 8.03(d, 1H), 7.76 (m, 2H), 7.47 (m, 1H), 7.31 (m, 3H), 7.19 (m, 1H), 5.27(s, 2H), 4.02 (s, 2H), 3.34 (m, 4H).

Example 4

(E)-N-(4-(3-Methyl-4-(6-methylpyridin-3-yloxy)phenylamino)quinazolin-6-yl)methyleneamino-2-methoxyacetamidine

MS ESI (+) m/z 456 (M+1) detected; ¹H NMR (400 MHz, CD3OD) δ8.63(s, 1H),8.5 (s, 1H), 8.41 (m, 2H), 8.12 (s, 1H), 7.79 (d, 1H), 7.7 (s, 1H), 7.61(d, 1H), 7.26 (m, 2H), 7.01 (d, 1H), 4.12 (s, 2H), 3.43 (s, 3H), 2.52(s, 3H), 2.12 (s, 3H).

Example 5

(E)-N-((4-(4-(3-Fluorobenzyloxy)-3-chlorophenylamino)-quinazolin-6-yl-methyleneamino)-acetamidine

MS ESI (+) m/z 463, 465 (M+1, Cl pattern) detected; ¹H NMR (400 MHz,CD₃OD) δ 8.64 (s, 1H), 8.52 (s, 1H), 8.42 (m, 2H), 7.92(s, 1H), 7.78 (d,1H), 7.6(d, 1H), 7.4 (m, 1H), 7.31 (d, 1H), 7.25 (d, 1H), 7.19 (d, 1H),7.06 (t, 1H), 5.21 (s, 2H), 2.06 (s, 3H).

Example 6

Preparation ofN4-[3-chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine

Step A:N-4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(2-phenyl-N-cyano-isourea)-quinazoline-4,6-diamineis prepared by stirringN-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine(0.63 g, 1.60 mmol) and diphenyl N-cyanocarbonimidate (1.0 g, 4.20mmol), in THF (20 mL), DCE (10 mL) and t-BuOH (10 mL) at roomtemperature for 2 hours, then at 80-90° C. for 3 hours. An additional0.40 g of diphenyl N-cyanocabonimidate is added. After stirring at80-90° C. for 3 hours, the reaction mixture is cooled to roomtemperature and concentrated. DCM (100 mL) is added, and the solid isisolated by filtration through a sintered glass funnel and dried,yielding 0.67 g (77.6%) of tan-yellow material.

Step B:N4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamineis prepared by adding 2-aminoethanol (10 mg, 0.164 mmol) to a mixture ofN-4-[3-chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(2-phenyl-N-cyanoisourea)-quinazoline-4,6-diamine(30 mg, 0.056 mmol) in 1:1 THF:isopropyl alcohol (2 mL) and heating to100° C. for 20 hours. The reaction mixture is concentrated under reducedpressure and purified by column chromatography (5% MeOH in ethylacetate) to provide the desired product as a white solid (19 mg, 74%).MS ESI (+) m/z 464, 466 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,acetone d₆) δ 8.52 (s, 1H), 8.43 (bs, 1H), 8.17 (d, 1H), 7.85 (dd, 1H),7.74 (d, 1H), 7.70 (d, 1H), 7.48 (m, 1H), 7.38 (d, 1H), 7.35 (d, 1h),7.21 (d, 1H), 7.12 (m, 1H), 5.29 (s, 2H), 4.42 (t, 2H), 3.93 (t, 2H).

Example 7

Preparation ofN4-[3-chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine

N4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamineis prepared by adding thioCDI (27 mg, 0.152 mmol) to a stirred solutionof N4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine(60 mg, 0.152 mmol) in 1:1 THF:DCM (8 mL). After 3 hours,2-amino-cyclopentanol (30 mg, 0.30 mmol) is added and the reactionmixture stirred for 4 hours. Solvent is removed under reduced pressureand the resulting thiourea is triturated with diethyl ether. The crudethiourea is suspended in THF (10 mL) and 1 M NaOH in water (0.38 mL) isadded followed by addition of a 1 M TsCl solution in THF (0.17 mL).After 1 hour, the reaction mixture is diluted with EtOAc and water, andthe phases separated. The aqueous phase is extracted with EtOAc and thecombined organic extracts are dried (Na₂SO₄) and concentrated.Purification by column chromatography (10:5:1 EtOAc:Hexanes:MeOH)provides the desired product (50 mg, 65%). MS APCI (+) m/z 506, 508(M+1, Cl pattern) detected; ¹H NMR (400 mHz, CD₃CN) δ 8.49 (s, 1H), 8.23(bs, 1H), 7.94 (s, 1H), 7.73 (m, 2H), 7.59 (m, 2H), 7.45 (m, 1H), 7.35(d, 1H), 7.29 (d, 1H), 7.19-7.10 (m, 3H), 5.23 (s, 2H), 5.18 (m, 1H),4.66 (m, 1H), 4.11 (d, 1H), 3.96 (d, 1H), 3.56 (dd, 2H).

The following compounds (Examples 8-56) are prepared as described inExample 7 using the appropriate quinazoline-6-aniline, and aminoalcohol.

Example 8

N4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(3,8-dioxa-1-aza-spiro[4.5]dec-1-en-2-yl)-quinazoline-4,6-diamine

MS APCI (+) m/z 534, 536 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,CD₃CN) δ 8.50 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.73 (d, 1H), 7.60(d, 1H), 7.47 (m, 1H), 7.34 (d, 1H), 7.29 (d, 1H), 7.15 (d, 1H), 7.11(d, 1H), 5.23 (s, 2H), 4.19 (m, 2H), 3.88 (m, 2H), 3.59 (m, 2H), 3.30(m, 2H), 1.78 (m, 5H).

Example 9

N6-(3,8-Dioxa-1-aza-spiro[4.5]dec-1-en-2-yl)-N4-[3-methyl-4-(6-methylpridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine

MS APCI (+) m/z 497 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.44 (s,1H), 8.19 (bs, 1H), 8.13 (d, 1H), 7.71 (m, 3H), 7.63 (dd, 1H), 7.29 (m,2H), 7.00 (d, 1H), 4.30 (s, 2H), 3.97 (m, 2H), 3.55 (m, 2H), 2.50 (s,3H), 2.27 (s, 3H), 1.96 (m, 2H), 1.77 (m, 2H).

Example 10

2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydropyrrolo[3,4-d]oxazole-5-carboxylicacid tert-butyl ester

MS APCI (+) m/z 568 (M+1) detected.

Example 11

N4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine

N4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamineis prepared from2-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydropyrrolo[3,4-d]oxazole-5-carboxylicacid tert-butyl ester by standard BOC deprotection methods using TFA inmethylene chloride. MS APCI (+) m/z 468 (M+1) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.42 (s, 1H), 8.21 (bs, 1H), 8.13 (d, 1H), 7.68 (m, 2H), 7.60(m, 2H), 7.28 (m, 2H), 6.98 (d, 1H), 5.18 (m, 1H), 4.74 (m, 1H), 3.34(d, 1H), 3.16 (d, 1H), 2.86 (m, 2H), 2.50 (s, 3H), 2.26 (s, 3H).

Example 12

1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydropyrrolo[3,4-d]oxazol-5-yl)-ethanone

1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydropyrrolo[3,4-d]oxazol-5-yl)-ethanoneis prepared fromN4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamineby standard acetylation methods using acetic anhydride in a mixture ofpyridine and methylene chloride. MS APCI (+) m/z 510 (M+1) detected; ¹HNMR (400 mHz, CD₃OD) δ 8.44 (s, 1H), 8.26 (d, 1H), 8.13 (d, 1H), 7.71(m, 2H), 7.63 (m, 2H), 7.28 (m, 2H), 7.00 (d, 1H), 5.28 (m, 1H), 4.89(m, 1H), 4.15 (d, 0.5H), 4.03 (m, 1H), 3.84 (d, 0.5H), 3.75 (m, 1H),3.47 (m, 1H), 2.50 (s, 3H), 2.27 (s, 3H), 2.09 (d, 3H).

Example 13

N4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(3-oxa-1,8-diaza-spiro[4.5]dec-1-en-2-yl)-quinazoline-4,6-diamine

N4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(3-oxa-1,8-diazaspiro[4.5]dec-1-en-2-yl)-quinazoline-4,6-diamineis prepared from2-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3-oxa-1,8-diaza-spiro[4.5]dec-1-ene-8-carboxylicacid tert-butyl ester by standard BOC deprotection methods using TFA inmethylene chloride. MS ESI (+) m/z 496 (M+1) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.43 (s, 1H), 8.39 (s, 1H), 8.12 (d, 1H), 7.70 (m, 3H), 7.61(dd, 1H), 7.28 (m, 2H), 6.98 (d, 1H), 3.45 (m, 2H), 3.32 (m, 2H), 3.25(m, 2H) 2.50 (s, 3H), 2.32 (m, 2H), 2.25 (s, 3H), 2.01 (m, 2H).

Example 14

1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3-oxa-1,8-diazaspiro[4.5]dec-1-en-8-yl)-ethanone

1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3-oxa-1,8-diaza-spiro[4.5]dec-1-en-8-yl)-ethanoneis prepared fromN4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(3-oxa-1,8-diaza-spiro[4.5]dec-1-en-2-yl)-quinazoline-4,6-diamineby standard acetylation methods using acetic anhydride in a mixture ofpyridine and methylene chloride.

Example 15

N6-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-N4-[3-methyl-4-(6-methylpyrdin-3-yloxy)-phenyl]-quinazoline-4,6-diamine

MS APCI (+) m/z 455 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.42 (s,1H), 8.12 (d, 1H), 7.70 (m, 4H), 7.60 (m, 3H), 7.28 (m, 2H), 6.99 (d,1H), 4.13 (s, 2H), 2.50 (s, 3H), 2.26 (s, 3H), 1.40 (s, 6H).

Example 16

N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(1-oxa-3,8-diazaspiro[4.5]dec-2-en-2-yl)-quinazoline-4,6-diamine

N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(1-oxa-3,8-diaza-spiro[4.5]dec-2-en-2-yl)-quinazoline-4,6-diamineis prepared from2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-1-oxa-3,8-diaza-spiro[4.5]dec-2-ene-8-carboxylicacid tert-butyl ester by standard BOC deprotection methods using TFA inmethylene chloride. MS ESI (+) m/z 516, 518 (M+1, Cl pattern) detected;¹H NMR (400 mHz, CDCl₃) δ 8.61 (s, 1H), 8.58 (d, 1H), 8.22 (bs, 1H),7.97 (d, 1H), 7.70 (m, 2H), 7.67 (d, 1H), 7.64 (dd, 1H), 7.35 (d, 1H),7.26 (m, 1H), 7.02 (d, 1H), 5.31 (s, 2H), 3.73 (s, 2H), 3.05 (m, 2H),2.96 (m, 2H), 1.97 (m, 2H), 1.80 (m, 2H).

Example 17

1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-1-oxa-3,8-diazaspiro[4.5]dec-2-en-8-yl)-ethanone

1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-1-oxa-3,8-diaza-spiro[4.5]dec-2-en-8-yl)-ethanoneis prepared from2-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-1-oxa-3,8-diazaspiro[4.5]dec-2-ene-8-carboxylicacid tert-butyl ester by standard BOC deprotection methods using TFA inmethylene chloride followed by standard acetylation methods using aceticanhydride in a mixture of pyridine and methylene chloride. MS ESI (+)m/z 538 (M+1) detected; ¹H NMR (400 mHz, CDCl₃) δ 8.68 (s, 1H), 8.28 (d,1H), 7.83 (d, 1H), 7.64 (s, 1H), 7.52 (d, 2H), 7.48 (d, 2H), 7.12 (m,3H), 6.93 (d, 1H), 3.69 (m, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 2.14 (s,3H), 2.02 (m, 2H), 1.78 (m, 2H), 1.30 (m, 2H), 0.87 (m, 2H).

Example 18

(4-Methyl-2-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-4,5-dihydrooxazol-4-yl)-methanol

MS ESI (+) m/z 471 (M+1) detected; 1H NMR (400 mHz, CDC1₃) δ 8.54 (s,1H), 8.19 (d, 1H), 8.16 (bs, 1H), 7.72 (m, 2H), 7.58 (dd, 1H), 7.48 (dd,1H), 7.19 (dd, 1H), 7.13 (d, 1H), 6.95 (d, 1H), 4.39 (d, 1H), 4.01 (d,1H), 3.42 (s, 2H), 2.52 (s, 3H), 2.29 (s, 3H), 1.39 (s, 3H).

Example 19

N4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(1,8-dioxa-3-aza-spiro[4.5]dec-2-en-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 534 (M+1) detected; ¹H NMR (400 mHz, CDC1₃) δ 8.64 (s,1H), 8.25 (bs, 1H), 7.78 (m, 2H), 7.60 (bs, 1H), 7.49 (d, 1H), 7.44 (d,1H), 7.35 (m, 2H), 7.23 (m, 2H), 7.02 (m, 1H), 6.94 (d, 1H), 5.15 (s,2H), 3.81 (m, 4H), 3.69 (m, 2H), 1.94 (m, 2H), 1.87 (m, 2H).

Example 20

N6-(1,8-Dioxa-3-azaspiro[4.5]dec-2-en-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine

MS ESI (+) m/z 497 (M+1) detected; ¹H NMR (400 mHz, CDC1₃) δ 8.67 (s,1H), 8.27 (d, 1H), 7.82 (d, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.50 (m,2H), 7.12 (m, 4H), 6.92 (d, 1H), 3.82 (m, 4H), 3.67 (m, 2H), 2.53 (s,3H), 2.29 (s, 3H), 1.95 (m, 2H), 1.88 (m, 2H).

Example 21

N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(5-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 467,469 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.60 (s, 1H), 8.52 (s, 1H), 8.20 (bs, 1H), 8.13 (s, 1H), 7.93(d, 1H), 7.87 (d, 1H), 7.82 (d, 1H), 7.71 (d, 2H), 7.38 (d, 1H), 5.60(s, 2H), 4.82 (m, 1H), 3.80 (m, 1H), 3.26 (m, 1H), 2.56 (s, 3H).

Example 22

N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 453, 455 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.54 (s, 1H), 8.47 (s, 1H), 8.07 (bs, 1H), 7.86 (d, 1H), 7.80(d, 1H), 7.76 (d, 1H), 7.66 (m, 2H), 7.32 (d, 1H), 5.55 (s, 2H), 4.38(m, 2H), 3.62 (m, 1H), 3.18 (m, 1H).

Example 23

N6-(5,5-Dimethyl-4,5-dihydrooxazol-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine

MS APCI (+) m/z 455 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.42 (s,1H), 8.17 (bs, 1H), 8.12 (d, 1H), 7.70 (d, 1H), 7.69 (s, 1H), 7.61 (dd,1H), 7.57 (dd, 1H), 7.28 (m, 2H), 6.98 (d, 1H), 3.64 (s, 2H), 2.50 (s,3H), 2.26 (s, 3H), 1.51 (s, 6H).

Example 24

N4-[3-Chloro-4-(pyridin-2-ytmethoxy)-phenyl]-N6-(4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 447, 449 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.53 (bs, 1H), 8.59 (d, 1H), 8.45 (s, 1H), 8.05 (bs, 1H),7.89 (m, 2H), 7.74 (d, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.38 (dd, 1H),7.25 (d, 1H), 5.29 (s, 2H), 4.38 (m, 2H), 3.62 (m, 2H).

Example 25

N4-[3-Chloro-4-(pyrdin-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 461, 463 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.51 (bs, 1H), 8.58 (d, 1H), 8.44 (s, 1H), 8.04 (bs, 1H),7.86 (m, 1H), 7.72 (d, 1H), 7.58 (m, 3H), 7.34 (m, 1H), 7.22 (d, 1H),5.27 (s, 2H), 4.74 (m, 1H), 3.72 (m, 1H), 3.15 (m, 1H), 1.32 (s, 3H).

Example 26

N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(1,8-dioxa-3-aza-spiro[4.5]dec-2-en-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 523, 525 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,CDCl₃) δ 8.64 (s, 1H), 7.78 (m, 2H), 7.60 (bs, 1H), 7.50 (d, 1H), 7.43(d, 1H), 7.35 (m, 1H), 7.23 (m, 2H), 7.02 (m, 1H), 6.95 (d, 1H), 5.15(s, 2H), 3.81 (m, 4H), 3.69 (m, 2H), 1.94 (m, 2H), 1.87 (m, 2H).

Example 27

N4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(5-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine

¹H NMR (400 mHz, CD₃OD) δ 8.50 (s, 1H), 8.12 (bs, 1H), 8.02 (d, 1H),7.97 (d, 1H), 7.60 (dd, 1H), 7.44 (m, 2H), 7.34 (d, 1H), 7.29 (d, 1H),7.14 (d, 1H), 7.10 (d, 1H), 5.22 (s, 2H), 4.79 (m, 1H), 3.87 (m, 1H),3.36 (m, 1H), 1.40 (d, 3H).

Example 28

N4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine

MS APCI (+) m/z 469 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.43 (s,1H), 8.26 (bs, 1H), 8.13 (d, 1H), 7.70 (m, 3H), 7.62 (m, 2H), 7.29 (m,2H), 7.08 (s, 1H), 7.00 (d, 1H), 5.25 (m, 1H), 4.82 (m, 1H), 4.17 (d,1H), 4.02 (d, 1H), 3.64 (m, 2H), 2.50 (s, 3H), 2.27 (s, 3H).

Example 29

(1RS,5SR)-1-(5-methyl-2-(4-(3-methyl-4-(6-methylpyridin-3-yloxy)phenylamino)quinazolin-6-ylamino)-4,5-dihydrooxazol-5-yl)ethanol

MS ESI (+) m/z 485 (M+1) detected; ¹H NMR (400 mHz, CDC1₃) δ 8.58 (s,1H), 8.22 (d, 1H), 8.17 (bs, 1H), 7.74 (d, 1H), 7.71 (d, 1H), 7.60 (dd,1H), 7.36 (d, 1H), 7.16 (dd, 1H), 7.10 (d, 1H), 6.94 (d, 1H), 4.02 (d,1H), 3.92 (m, 1H), 3.55 (d, 1H), 2.52 (s, 3H), 2.28 (s, 3H), 1.45 (s,3H), 1.22 (m, 4H).

Example 30

N6-(4,5-Dihydrooxazol-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine

MS ESI (+) m/z 427 (M+1) detected; ¹H NMR (400 mHz, DMSO-D₆) δ 9.53 (s,1H), 8.45 (s, 1H), 8.18 (d, 1H), 7.80 (s, 1H), 7.72 (d, 1H), 7.65 (d,1H), 7.21 (m, 3H), 6.96 (d, 1H), 4.38 (m, 2H), 3.64 (m, 2H), 2.51 (s,3H), 2.20 (s, 3H).

Example 31

(2-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-4-methyl-4,5-dihydro-oxazol-4-yl)-methanol

MS ESI (+) m/z 491, 493 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,CDCl₃) δ 8.57 (s, 1H), 8.56 (s, 1H), 8.13 (bs, 1H), 7.97 (d, 1H), 7.81(m, 1H), 7.73 (m, 2H), 7.61 (dd, 1H), 7.44 (dd, 1H), 7.29 (m, 1H), 7.04(d, 1H), 5.30 (s, 2H) 3.64 (d, 1H), 3.52 (d, 1H), 3.43 (s, 2H), 1.26 (s,3H).

Example 32

(1RS,5SR)-1-(2-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)quinazolin-6-ylamino)-5-methyl-4,5-dihydrooxazol-5-yl)ethanol

MS ESI (+) m/z 505, 507 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,CDCl₃) δ 8.60 (s, 1H), 8.58 (s, 1H), 8.12 (bs, 1H), 7.95 (d, 1H), 7.77(m, 1H), 7.72 (d, 1H), 7.69 (d, 1H), 7.63 (dd, 1H), 7.25 (m, 2H), 7.02(d, 1H), 5.30 (s, 2H), 4.07 (d, 1H), 3.98 (q, 1H), 3.56 (d, 1H), 1.45(s, 3H), 1.22 (d, 3H).

Example 33

N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4.4-dimethyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine

MS APCI (+) m/z 481, 483 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.52 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.96 (bs, 1H), 7.86(d, 1H), 7.81 (d, 1H), 7.78 (d, 1H), 7.65 (d, 1H), 7.32 (d, 1H), 5.55(s, 2H), 3.17 (d, 2H), 1.28 (s, 6H).

Example 34

(1-RS,5SR)-1-(2-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-ylamino)-5-methyl-4,5-dihydrooxazol-5-yl)ethanol

MS ESI (+) m/z 522, 524 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,CDCl₃) δ 8.57 (s, 1H), 8.10 (bs, 1H), 7.91 (d, 1H), 7.70 (d, 1H), 7.65(dd, 1H), 7.36 (m, 1H), 7.30 (m, 1H), 7.24 (m, 2H), 7.00 (m, 1H), 6.98(d, 1H), 5.16 (s, 2H), 4.05 (d, 1H), 3.95 (q, 1H), 3.55 (d, 1H), 1.45(s, 3H), 1.21 (d, 3H).

Example 35

N6-(5-Methyl-4,5-dihydrooxazol-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine

MS APCI (+) m/z 441 (M+1) detected; ¹H NMR (400 mHz, DMSO-D₆) δ 9.51 (s,1H), 8.45 (s, 1H), 8.18 (d, 1H), 7.80 (s, 1H), 7.69 (m, 3H), 7.23 (m,2H), 6.96 (d, 1H), 4.77 (m, 1H), 4.13 (m, 1H), 6.73 (m, 1H), 2.44 (s,3H), 2.20 (s, 3H), 1.36 (d, 3H).

Example 36

N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine

MS APCI (+) m/z 467, 469 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.86 (d, 1H), 7.81(d, 1H), 7.77 (d, 1H), 7.69 (m, 3H), 7.32 (d, 1H), 7.02 (s, 1H), 5.54(s, 2H), 4.47 (m, 1H), 3.99 (m, 1H), 3.90 (m, 1H), 1.18 (d, 3H).

Example 37

N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(1,8-dioxa-3-aza-spiro[4.5]dec-2-en-2-yl)-quinazoline-4,6-diamine

MS APCI (+) m/z 517, 519 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,CDCl₃) δ 8.66 (s, 1H), 8.60 (d, 1H), 7.87 (s, 1H), 7.81 (d, 1H), 7.76(m, 1H), 7.66 (d, 1H), 7.51 (m, 2H), 7.44 (d, 1H), 7.25 (m, 1H), 7.01(d, 1H), 5.30 (s, 2H), 3.82 (m, 4H), 3.75 (m, 1H), 3.69 (m, 1H), 1.95(m, 2H), 1.87 (m, 2H).

Example 38

N6-(4-Methyl-4,5-dihydrooxazol-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine

MS APCI (+) m/z 441 (M+1) detected; ¹H NMR (400 mHz, DMSO-D₆) δ 9.51 (s,1H), 8.44 (s, 1H), 8.15 (d, 1H), 8.05 (bs, 1H), 7.79 (s, 1H), 7.71 (d,1H), 7.62 (m, 2H), 7.20 (m, 2H), 6.99 (s, 1H), 6.93 (d, 1H), 4.45 (m,1H), 4.02 (m, 1H), 3.87 (m, 1H), 2.41 (s, 3H), 2.18 (s, 3H), 1.17 (d,3H).

Example 39

N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 447, 449 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.53 (bs, 1H), 8.59 (d, 1H), 8.45 (s,.lH), 8.05 (bs, 1H),7.89 (m, 2H), 7.74 (d, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.38 (dd, 1H),7.25 (d, 1H), 5.29 (s, 2H), 4.38 (m, 2H), 3.62 (m, 2H).

Example 40

N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 461, 463 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.51 (bs, 1H), 8.58 (d, 1H), 8.44 (s, 1H), 8.04 (bs, 1H),7.86 (m, 1H), 7.72 (d, 1H), 7.58 (m, 3H), 7.34 (m, 1H), 7.22 (d, 1H),5.27 (s, 2H), 4.74 (m, 1H), 3.72 (m, 1H), 3.15 (m, 1H), 1.32 (s, 3H).

Example 41

N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine

MS APCI (+) m/z 495, 497 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.47 (s, 1H), 8.23 (br. s, 1H), 7.95 (d, 1H), 7.83 (d, 1H),7.71 (d, 1H), 7.66 (dd, 1H), 7.63 (d, 1H), 7.59 (dd, 1H), 7.21 (d, 1H),5.50 (s, 2H), 4.19 (d, 1H), 4.05 (d, 1H), 3.65 (m, 2H), 3.19 (m, 2H).

Example 42

N4-[3-Methyl1-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 475 (M+1) detected; ¹H NMR (400 mHz, CD₃OD) δ 8.37 (s,1H), 8.25 (br s, 1H), 7.83 (d, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 7.59 (m,1H), 7.52 (m, 2H), 7.07 (d, 1H), 5.46 (s, 2H), 4.17 (d, 1H), 4.02 (d,1H), 3.64 (m, 2H), 2.34 (m, 5H).

Example 43

N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(1,8-dioxa-3-aza-spiro[4.5]dec-2-en-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 523, 525 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,CDCl₃) δ 8.64 (s, 1H), 7.78 (m, 2H), 7.60 (bs, 1H), 7.50 (d, 1H), 7.43(d, 1H), 7.35 (m, 1H), 7.23 (m, 2H), 7.02 (m, 1H), 6.95 (d, 1H), 5.15(s, 2H), 3.81 (m, 4H), 3.69 (m, 2H), 1.94 (m, 2H), 1.87 (m, 2H).

Example 44

N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(5-methyl-4,5-dihydrooxazol1-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 461, 463 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.51 (s, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.04 (m, 2H), 7.86(m, 1H), 7.63 (m, 4H), 7.34 (m, 1H), 7.22 (d, 1H), 5.27 (s, 2H), 4.74(m, 1H), 3.72 (m, 1H), 3.15 (m, 1H), 1.34 (d, 3H).

Example 45

N4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(4-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 478 (M+1) detected; ¹H NMR (400 mHz, DMSO-D₆) δ 9.51 (s,1H), 8.46 (s, 1H), 8.06 (m, 2H), 7.76 (d, 1H), 7.64 (d, 1H), 7.47 (m,2H), 7.32 (m, 2H), 7.24 (d, 1H), 7.18 (m, 1H), 5.25 (s, 2H), 4.47 (m,1H), 3.95 (m, 1H), 3.17 (m, 1H), 1.19 (d, 3H).

Example 46

N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine

N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamineis prepared from2-{4-[3-chloro-4-(thiazol-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydro-pyrrolo[3,4-d]oxazole-5-carboxylicacid tert-butyl ester by standard BOC deprotection methods using TFA inmethylene chloride. MS APCI (+) m/z 494, 496 (M+1, Cl pattern) detected;¹H NMR (400 mHz, CD₃OD) δ 8.44 (s, 1H), 8.19 (br. s, 1H), 7.96 (d, 1H),7.83 (d, 1H), 7.67 (m, 3H), 7.58 (dd, 1H), 7.22 (d, 1H), 5.50 (s, 2H),5.17 (m, 1H), 4.76 (m, 1H), 3.32 (d, 1H), 3.16 (d, 1H), 2.85 (m, 2H).

Example 47

N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine

N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamineis prepared from2-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydro-pyrrolo[3,4-d]oxazole-5-carboxylicacid tert-butyl ester by standard BOC deprotection methods using TFA inmethylene chloride. MS APCI (+) m/z 488, 490 (M+1, Cl pattern) detected;¹H NMR (400 mHz, CD₃OD) δ 8.56 (d, 1H), 8.44 (s, 1H), 8.21 (br. s, 1H),7.91 (m, 2H), 7.70 (m, 2H), 7.63 (d, 1H), 7.57 (d, 1H), 7.39 (m, 1H),7.16 (d, 1H), 5.28 (s, 2H), 5.17 (m, 1H), 4.78 (m, 1H), 3.34 (d, 1H),3.16 (d, 1H), 2.84 (m, 2H).

Example 48

(2-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-ylamino}-4-methyl-4,5-dihydro-oxazol-4-yl)-methanol

MS ESI (+) m/z 508, 510 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,CDCl₃) δ 8.57 (s, 1H), 8.14 (s, 1H), 7.93 (d, 1H), 7.74 (d, 1H), 7.63(dd, 1H), 7.37 (m, 2H), 7.25 (m, 2H), 7.01 (m, 2H), 5.17 (s, 2H), 4.38(d, 1H), 4.00 (d, 1H), 3.65 (d, 1H), 3.48 (d, 1H), 1.38 (s, 3H).

Example 49

N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(6-oxa-4-aza-spiro[2.4]hept-4-en-5-yl)-quinazoline-4,6-diamine

MS APCI (+) m/z 473, 475 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,CD₃OD) δ 8.56 (d, 1H), 8.45 (s, 1H), 8.21 (s, 1H), 7.98 (d, 1H), 7.92(m, 1H), 7.72 (m, 2H), 7.63 (m, 2H), 7.40 (m, 1H), 7.18 (d, 1H), 5.28(s, 2H), 4.36 (s, 2H), 1.12 (m, 2H), 0.81 (m, 2H).

Example 50

(2-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-4-hydroxymethyl-4,5-dihydro-oxazol-4-yl)-methanol

MS ESI (+) m/z 507, 509 (M+1, Cl pattern) detected; ¹H NMR (400 mHz,DMSO-D₆) δ 9.47 (s, 1H), 8.60 (d, 1H), 8.46 (s, 1H), 8.08 (s, 1H), 7.89(m, 1H), 7.71 (m, 2H), 7.58 (d, 1H), 7.37 (m, 1H), 7.25 (d, 1H), 5.29(s, 2H), 4.34 (m, 2H), 3.29 (s, 4H).

Example 51

(R)-1-((S)-2-(4-(3-chloro-4-(thiazol-2-ylmethoxy)phenylamino)quinazolin-6-ylamino)-4,5-dihydrooxazol-4-yl)ethanol

(R)-1-((S)-2-(4-(3-chloro-4-(thiazol-2-ylmethoxy)phenylamino)quinazolin-6-ylamino)-4,5-dihydrooxazol-4-yl)ethanolis prepared from (1R,4S)-N6-[4-(1-tert-butoxyethyl)-4,5-dihydrooxazol-2-yl]-N4-[3-chloro-4-(thiazol-2-ylmethoxy)-phenyl]-quinazoline-4,6-diamineby standard deprotection methods using TFA in methylene chloride. MS ESI(+) m/z 497, 499 (M+1, Cl pattern) detected; ¹H NMR (400 mHz, DMSO-D₆) δ9.53 (s, 1H), 8.47 (s, 1H), 8.08 (d, 1H), 7.87 (d, 1H), 7.80 (d, 1H),7.76 (dd, 1H), 7.66 (m, 2H), 7.33 (d, 1H), 5.55 (s, 2H), 4.81 (m, 1H),4.37 (m, 1H), 4.20 (m, 1H), 3.83 (m, 1H), 3.63 (m, 1H), 1.06 (d, 3H).

Example 52

(R)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

Prepared using (R)-2-aminopropan-1-o1. MS APCI (+) m/z 467, 469 (M+1, Clpattern) detected; ¹H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s,1H), 8.09 (s, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.69 (m,3H), 7.32 (d, 1H), 7.02 (s, 1H), 5.54 (s, 2H), 4.47 (m, 1H), 3.99 (m,1H), 3.90 (m, 1H), 1.18 (d, 3H).

Example 53

(S)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

Prepared using (S)-2-amino-propan-1-o1. MS APCI (+) m/z 467, 469 (M+1,Cl pattern) detected; ¹H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s,1H), 8.09 (s, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.69 (m,3H), 7.32 (d, 1H), 7.02 (s, 1H), 5.54 (s, 2H), 4.47 (m, 1H), 3.99 (m,1H), 3.90 (m, 1H), 1.18 (d, 3H).

Example 54

(S)-N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(5-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

Prepared using (S)-1-amino-propan-2-o1. MS ESI (+) m/z 461, 463 (M+1, Clpattern) detected; ¹H NMR (400 mHz, DMSO-D6) δ 9.51 (s, 1H), 8.58 (s,1H), 8.44 (s, 1H), 8.04 (m, 2H), 7.86 (m, 1H), 7.63 (m, 4H), 7.34 (m,1H), 7.22 (d, 1H), 5.27 (s, 2H), 4.74 (m, 1H), 3.72 (m, 1H), 3.15 (m,1H), 1.34 (d, 3H).

Example 55

(R)-N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(5-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

Prepared using (R)-1-amino-propan-2-o1. MS ESI (+) m/z 461, 463 (M+1, Clpattern) detected; ¹H NMR (400 mHz, DMSO-D6) δ 9.51 (s, 1H), 8.58 (s,1H), 8.44 (s, 1H), 8.04 (m, 2H), 7.86 (m, 1H), 7.63 (m, 4H), 7.34 (m,1H), 7.22 (d, 1H), 5.27 (s, 2H), 4.74 (m, 1H), 3.72 (m, 1H), 3.15 (m,1H), 1.34 (d, 3H).

Example 56

N4-[4-(5-Chloropyridin-3-yloxy)-3-methyl-phenyl]-N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

MS ESI (+) m/z 475 477 (m+1, Cl pattern) detected; ¹H NMR (400 mHz, DMSOd₆) 9.62 (bs, 1H), 8.49 (s, 1H), 8.37 (d, 1H), 8.29 (d, 1H),8.05 (bs,1H), 7.87 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.41 (m, 1H), 7.10 (d,1H), 4.11 (s, 2H), 2.19 (s, 3H), 1.29 (s, 6H).

Example 57

N6-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-N4-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine

MS ESI (+) m/z 441 (m+1) detected; ¹H NMR (400 mHz, DMSO d₆) 9.54 (bs,1H), 8.46 (s, 1H), 8.33 (d, 1H), 8.29 (d, 1H),8.00 (bs, 1H), 7.84 (s,1H), 7.77 (d, 1H), 7.65 (d, 1H), 7.37 (m, 1H), 7.26 (m, 1H), 7.03 (d,1H), 4.07 (s, 2H), 2.19 (s, 3H), 1.28 (s, 6H).

Example 58

N6-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-N4-[4-(5-fluoro-pyridin-3-yloxy)-3-methyl-phenyl]-quinazoline-4,6-diamine

MS ESI (+) m/z 459 (m+1) detected; ¹H NMR (400 mHz, DMSO d₆) 9.70 (bs,1H),8.51 (s, 1H), 8.43 (d, 1H), 8.20 (d, 1H),8.11 (bs, 1H), 7.86 (s,1H), 7.80 (d, 1H), 7.69 (m 2H), 7.29 (d, 1H), 7.11 (d, 1H), 4.61 (s,2H), 2.20 (s, 3H), 1.30 (s, 6H).

The amino alcohols used in the above examples are either known compoundsor are prepared as described below.

Example 59

Preparation of (4-aminotetrahydropyran-4-yl)-methanol

(4-Amino-tetrahydropyran-4-yl)-methanol is prepared by adding LAH (99%,1.2 g), portionwise, to a stirred mixture of4-aminotetrahydropyran-4-carboxylic acid hydrochloride (2.0 g, 11.0mmol) in THF (30 mL) at 0° C. Upon completion of addition, the reactionmixture is warmed to room temperature and stirred for 1 hour. Thereaction mixture is cooled to 0° C. and cautiously quenched by theportionwise addition of Na₂SO₄.10H₂O (4 g). The reaction mixture isdiluted with ethyl acetate, warmed to room temperature, and filteredthrough Celite to give the desired product.

Example 60

Preparation of 4-aminomethyl-4-hydroxypiperidine-1-carboxylic acidtert-butyl ester

4-Aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester isprepared from 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butylester (Bourrain et al Bioorg. Med. Chem. Lett. 9(23):3369-3374 (1999)).Concentrated aqueous NH₄OH (6 mL) is added to a solution of1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (0.50 g,2.3 mmol) in MeOH (4 mL) at 0° C. The reaction mixture is removed fromthe cooling and allowed to warm to room temperature. After 7 hours, thereaction mixture is concentrated under reduced pressure to afforddesired product as a white solid.

Example 61

Preparation of 4-aminomethyltetrahydro-pyran-4-o1

4-Aminomethyl-tetrahydro-pyran-4-ol is prepared from1,6-dioxa-spiro[2.5]octane. A MeOH (3.5 mL) solution of1,6-dioxa-spiro[2.5]octane (0.19 g, 1.7 mmol) is added to concentratedaqueous NH₄OH (4.3 mL) at 0° C. The reaction mixture is warmed to roomtemperature and stirred for 16 hours. The reaction mixture isconcentrated under reduced pressure and purified by columnchromatography (10% MeOH, 2% Et₃N in DCM) to afford 90 mg (41%) of thedesired product as a white solid.

Example 62

Preparation of (2RS, 3SR)-1-amino-2-methylbutane-2, 3-diol

(2RS, 3SR)-1-Amino-2-methylbutane-2, 3-diol is prepared from acetic acid1,2-dimethyl-allyl ester. mCPBA (17 g, 69 mmol) is slowly added to astirred solution of acetic acid 1,2-dimethylallyl ester (6.80 g, 53.1mmol) in methylene chloride (500 mL). After 4 hours, the reaction iswashed with saturated NaHCO₃, water and brine. The organic layer isdried (Na₂SO₄) and concentrated under reduced pressure. Purification bycolumn chromatography (20% diethyl ether in pentane; repeated) gives(1-RS, 2-SR)-acetic acid 1-(-2-methyloxiranyl)-ethyl ester (3.45 g,45%). A small amount of (1-RS, 2-SR)-acetic acid1-(-2-methyloxiranyl)-ethyl ester was converted to (2RS,3SR)-3,4-epoxy-3-methyl-2-butanaol (JACS (1990) 112(13):5285) bytreatment with K₂CO₃ in MeOH to confirm the relative stereochemistry ofthis racemic material. K₂CO₃ (1.54 g, 11.1 mmol) is added to a stirredsolution of acetic acid (R*)-1-((S*)-2-methyl-oxiranyl)-ethyl ester(1.70 g, 11.8 mmol) in MeOH (12 mL). After 1 hour, the reaction mixtureis filtered through Celite. The filtrate is added slowly via an additionfunnel to 20 mL concentrated aqueous NH₄OH. After stirring 16 hours, thereaction mixture is concentrated under reduced pressure and purified bycolumn chromatography (20% MeOH, 2% Et₃N in DCM) to afford 0.97 g (69%)of the desired product as a light yellow oil.

Example 63 Preparation ofN⁴-[3-chloro-4-(3-fluorobenzyloxy)-phenyl]-N⁶-(4,5-dihydro-oxazol-2-yl)-N⁶-methylquinazoline-4,6-diamine

Step A: A solution ofN⁴-[3-chloro-4-(3-fluorobenzyloxy)-phenyl]-quinazoline-4,6-diamine (1.09g, 2.76 mmol) and di-t-butyl dicarbonate (2.0 g, 3.3 equiv) was heatedin t-BuOH:DCE (1:1) in a sealed tube at 90-95° C. for 20 minutes, thencooled to room temperature. The volatiles were removed under reducedpressure, and the product was purified by silica gel chromatography (60%EtOAc/hexanes), affording a yellow solid (670 mg, 49%).

Step B: The purified material from Step A was taken up in THF (5-10 mL)at 0° C., and LAH (1.0 M solution in THF, 1 equivalent) was added. Thesolution was refluxed for 1 hour, then cooled to room temperature. Thereaction was diluted with THF and quenched by the portionwise additionof excess sodium sulfate decahydrate. The reaction was filtered and theproduct was purified by silica gel chromatography (100% EtOAc),affording a yellow solid.

Step C: The purified material from Step B (63 mg, 0.15 mmol) was takenup in THF (3 mL) and 2-chloroethyl isocyanate (32 μL, 2.4 equivalents)was added. The reaction was heated at 50° C. until a heavy precipitateformed. The product is obtained as a bright yellow solid by vacuumfiltration (26 mg, 33%).

Step D: The material from Step C was taken up in MeCN (2 mL) and 40% KFon alumina (130 mg, 18 equivaltnets) was added. The mixture was refluxedfor 12 hours, diluted with MeCN, and filtered through Celite. Silica gelchromatography affordedN⁴-[3-chloro-4-(3-fluorobenzyloxy)-phenyl]-N⁶-(4,5-dihydro-oxazol-2-yl)-N⁶-methyl-quinazoline-4,6-diamine(67 mg, 25%).

Additional compounds of the present invention include:

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groups.

1. A compound including resolved enantiomers, diastereomers, solvatesand pharmaceutically acceptable salts thereof, said compound comprisingFormula I:

wherein A is bonded to at least one of the carbons at positions 5, 6, 7or 8 of the bicyclic ring and wherein the bicyclic ring is substitutedby zero, one or two independent R³ groups; X is N, CH, CF or C—CN; A isQ or Z;

R¹ is a substituted or unsubstituted, monocyclic or bicyclic, aryl orheteroaryl moiety; R² is H or a substituted or unsubstituted C₁₋₈ alkyl,allyl, substituted benzyl R³ is hydrogen, halogen, cyano, nitro, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, partially unsaturated heterocylyl, heterocyclylalkyl,—NR⁴SO₂R⁵ —SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁴C(O)OR⁵,—NR⁴C(O)R⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶, —OR⁶, —S(O)R⁵, —SO₂R⁵, orSR⁶, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, partiallyunsaturated heterocylyl, and heterocyclylalkyl is optionally substitutedwith one to five groups independently selected from the group consistingof oxo, halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, —NR⁴SO₂R⁵, —SO₂NR⁶R⁴, —C(O)R⁶,—C(O)OR⁶, —OC(O)R⁶, —NR⁴C(O)OR⁵, —NR⁴C(O)CR⁶, —C(O)NR⁴R⁶, —NR⁴R⁶,—NR⁴C(O)NR⁴R⁶, —NR⁴C(NCN)NR⁴R⁶, —OR⁶, —S(O)R⁵, —SO₂R⁵, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R¹⁰ ishydrogen, halogen, cyano, nitro, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, partiallyunsaturated heterocyclyl —NR⁴SO₂R⁵ —SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶,—OC(O)R⁶, —NR⁴C(O)OR⁵, —NR⁴C(O)R⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶,—OR⁶, —S(O)R⁵, —SO₂R⁵, or SR⁶, wherein said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, or partially unsaturatedheterocyclyl is optionally substituted with one to five groupsindependently selected from the group consisting of oxo, halogen, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR⁴SO₂R⁵, —SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶,—OC(O)R⁶, —NR⁴C(O)OR⁵, —NR⁴C(O)CR⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶,—NR⁴C(NCN)NR⁴R⁶, —OR⁶, —S(O)R⁵—SO₂R⁵, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein g is 1 to3 and each R¹⁰ can be the same or different, or one or more of said R¹⁰groups are independently joined together with the atoms to which theyare attached to complete a 3 to 10 membered cycloalkyl ring orheterocycloalkyl ring optionally containing one or more additionalheteroatoms selected from the group consisting of O, S, SO, SO₂ and NR⁶,where each ring carbon is optionally substituted with one to threegroups independently selected from the group consisting of halogen,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, provided said ringdoes not contain two adjacent O or two adjacent S atoms;

wherein when R⁶═H then Z further includes

and wherein Z includes one or more R⁸ or R⁹ groups, wherein said R⁸ andR⁹ groups may be bonded to the same or different atoms; W and V areindepenently selected from the group consisting of O, NR⁶, S, SO, SO₂,CR⁷R⁸, and CR⁸R⁹, and Y is selected from the group consisting of S, SO,SO₂, CR⁷CR⁸, and CR⁸R⁹, provided that when W is O, NR⁶, S, SO, or SO₂,then V is CR⁸R⁹, and when V is O, NR⁶, S, SO, or SO₂, then W and Y areeach CR⁸R⁹; R⁴ is H or C₁₋₆ alkyl; R⁵ is trifluoromethyl, C₁-C₁₀ alkyl,C₃-C₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, or partially unsaturated heterocycle,wherein said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl, andheterocyclylalkyl is optionally substituted with one to five groupsindependently selected from the group consisting of oxo, halogen, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, cyano, nitro, OR⁶, NR⁴R⁶, SR⁶, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R⁶, R⁸ and R⁹ areindependently selected from the group consisting of hydrogen,trifluoromethyl, C₁-C₁₀ alkyl, (CH₂)₀₋₄C₃-C₁₀ cycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, partiallyunsaturated heterocyclyl and heterocyclylalkyl, wherein said alkyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, partiallyunsaturated heterocyclyl, and heterocyclylalkyl is optionallysubstituted with one to five groups independently selected from thegroup consisting of oxo, halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano, nitro, OR⁶,NR⁶R⁸, SR⁶, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partiallyunsaturated heterocyclyl and heterocyclylalkyl; R⁷ is hydrogen, halogen,cyano, nitro, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, partially unsaturatedheterocycle, —NR⁴SO₂R⁵—SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶,—NR⁴C(O)OR⁵, —NR⁴C(O)R⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶, —OR⁶,—S(O)R⁵, —SO₂R⁵, or SR⁶, wherein said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl heterocyclyl, and partially unsaturatedheterocyclyl is optionally substituted with one to five groupsindependently selected from the group consisting of oxo, halogen, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, —NR⁴SO₂R⁵, —SO₂NR⁶R⁴, —C(O)R⁶, —C(O)OR⁶,—OC(O)R⁶, —NR⁴C(O)OR⁵, —NR⁴C(O)CR⁶, —C(O)NR⁴R⁶, —NR⁴R⁶, —NR⁴C(O)NR⁴R⁶,—NR⁴C(NCN)NR⁴R⁶, —OR⁶, —S(O)R⁵, —SO₂R⁵, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl andheterocyclylalkyl; or R⁴ and R⁶ together with the atoms to which theyare attached may be independently joined to complete a 3 to 10 memberedcycloalkyl ring or heterocycloalkyl ring optionally containing one ormore additional heteroatoms selected from the group consisting of O, S,SO, SO₂ and NR⁶, wherein each ring carbon is optionally substituted withone to three groups independently selected from the group consisting ofhalogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partiallyunsaturated heterocyclyl and heterocyclylalkyl, provided said ring doesnot contain two adjacent O or two adjacent S atoms; or R⁶ and R⁸together with the atoms to which they are attached may be independentlyjoined to complete a 3 to 10 membered cycloalkyl ring orheterocycloalkyl ring optionally containing one or more additionalheteroatoms selected from the group consisting of O, S, SO, SO₂ and NR⁶,wherein each ring carbon is optionally substituted with one to threegroups independently selected from the group consisting of halogen,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl andheterocyclylalkyl, provided said ring does not contain two adjacent O ortwo adjacent S atoms; or R⁷ and R⁸ together with the atoms to which theyare attached may be independently joined to complete a 3 to 10 memberedcycloalkyl ring or heterocycloalkyl ring optionally containing one ormore additional heteroatoms selected from the group consisting of O, S,SO, SO₂ and NR⁶, wherein each ring carbon is optionally substituted withone to three groups independently selected from the group consisting ofhalogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano, nitro, trifluoromethyl,difluoromethoxy, trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partiallyunsaturated heterocyclyl and heterocyclylalkyl; provided said ring doesnot contain two adjacent O or two adjacent S atoms; or R⁸ and R⁹together with the atoms to which they are attached may be independentlyjoined to complete a 3 to 10 membered cycloalkyl ring orheterocycloalkyl ring optionally containing one or more additionalheteroatoms selected from the group consisting of O, S, SO, SO₂ and NR⁶,wherein each ring carbon may be optionally substituted with one to threegroups independently selected from the group consisting of halogen,C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy,trifluoromethoxy, azido, aryl, OR⁸, NR⁶R⁸, SR⁶, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl andheterocyclylalkyl, provided said ring does not contain two adjacent O ortwo adjacent S atoms; or R⁶ and R¹⁰ together with the atoms to whichthey are attached may be independently joined to complete a 3 to 10membered cycloalkyl ring or heterocycloalkyl ring optionally containingone or more additional heteroatoms selected from the group consisting ofO, S, SO, SO₂ and NR⁶, wherein each ring carbon may be optionallysubstituted with one to three groups independently selected from thegroup consisting of halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, OR⁸,NR⁶R⁸, SR⁶, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,partially unsaturated heterocyclyl and heterocyclylalkyl, provided saidring does not contain two adjacent O or two adjacent S atoms; or R⁸ andR¹⁰ together with the atoms to which they are attached may beindependently joined to complete a 3 to 10 membered cycloalkyl ring orheterocycloalkyl ring optionally containing one or more additionalheteroatoms selected from the group consisting of O, S, SO, SO₂ and NR⁶,wherein each ring carbon may be optionally substituted with one to threegroups independently selected from halogen, C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl,cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,aryl, OR⁸, NR⁶R⁸, SR⁶, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl,provided said ring does not contain two adjacent O or two adjacent Satoms.
 2. The compound of claim 1, wherein R² is a C₁₋₈ alkyl having aterminal carbon atom bound to one of the ring atoms of R¹.
 3. Thecompound of claim 1, wherein A is bonded to at least one of the carbonsat the 6 or 7 position of the bicyclic ring.
 4. The compound of claim 1,wherein R² is hydrogen, R³ is hydrogen or OR⁶, and X is N or C—CN. 5.The compound of claim 1, wherein R² is hydrogen.
 6. The compound ofclaim 1, wherein Z is

W is O and V is CR⁸R⁹.
 7. The compound of claim 4, wherein Z is

W is O and V is CR⁸R⁹.
 8. The compound of claim 1, wherein A is Q. 9.The compound of claim 4, wherein A is Q.
 10. A compound according toclaim 1 which is selected fromN6-(4,5-dihydrooxazol-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine,(2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-4,5-dihydrooxazol-4-yl)-methanol,(R)-N4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(5-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine,(S)-N4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(5-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine,(S)-N4-[3-chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine,(R)-N4-[3-chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine,N4-[3-chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine,N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine.11. A method of treating hyperproliferative diseases in a mammalcomprising administering a therapeutically effective amount of thecompound defined in claim 1 to said mammal.
 12. A method of treatinghyperproliferative diseases in a mammal comprising administering atherapeutically effective amount of the compound defined in claim 2 tosaid mammal.
 13. A method of treating hyperproliferative diseases in amammal comprising administering a therapeutically effective amount ofthe compound defined in claim 3 to said mammal.
 14. A method of treatinghyperproliferative diseases in a mammal comprising administering atherapeutically effective amount of the compound defined in claim 4 tosaid mammal.
 15. A method of treating hyperproliferative diseases in amammal comprising administering a therapeutically effective amount ofthe compound defined in claim 5 to said mammal.
 16. A method of treatinghyperproliferative diseases in a mammal comprising administering atherapeutically effective amount of the compound defined in claim 6 tosaid mammal.
 17. A method of treating hyperproliferative diseases in amammal comprising administering a therapeutically effective amount ofthe compound defined in claim 7 to said mammal.
 18. A method of treatinghyperproliferative diseases in a mammal comprising administering atherapeutically effective amount of the compound defined in claim 8 tosaid mammal.
 19. A method of treating hyperproliferative diseases in amammal comprising administering a therapeutically effective amount ofthe compound defined in claim 9 to said mammal.
 20. The compound ofclaim 6, wherein X is N or C—CN, R³ is hydrogen or OR⁶ and R² ishydrogen.
 21. The compound of claim 20, wherein R³ is hydrogen.
 22. Thecompound of claim 20, wherein R⁶ is hydrogen.
 23. The compound of claim21, wherein R⁶ is hydrogen.
 24. The compound of claim 20, wherein Z isbonded to at least one of the carbons at the 6 or 7 position of thebicyclic ring.
 25. The compound of claim 21, wherein Z is bonded to atleast one of the carbons at the 6 or 7 position of the bicyclic ring.26. The compound of claim 22, wherein Z is bonded to at least one of thecarbons at the 6 or 7 position of the bicyclic ring.
 27. The compound ofclaim 23, wherein Z is bonded to at least one of the carbons at the 6 or7 position of the bicyclic ring.
 28. The compound of claim 24, wherein Zis bonded to the carbon at the 6 position of the bicyclic ring.
 29. Thecompound of claim 25, wherein Z is bonded to the carbon at the 6position of the bicyclic ring.
 30. The compound of claim 26, wherein Zis bonded to the carbon at the 6 position of the bicyclic ring.
 31. Thecompound of claim 27, wherein Z is bonded to the carbon at the 6position of the bicyclic ring.
 32. The compound of claim 22, wherein Vis CH₂.
 33. The compound of claim 23, wherein V is CH₂.
 34. The compoundof claim 26, wherein V is CH₂.
 35. The compound of claim 27, wherein Vis CH₂.
 36. The compound of claim 30, wherein V is CH₂.
 37. The compoundof claim 31, wherein V is CH₂.
 38. The compound of claim 32, wherein R⁹is hydrogen.
 39. The compound of claim 33, wherein R⁹ is hydrogen. 40.The compound of claim 34, wherein R⁹ is hydrogen.
 41. The compound ofclaim 35, wherein R⁹ is hydrogen.
 42. The compound of claim 36, whereinR⁹ is hydrogen.
 43. The compound of claim 37, wherein R⁹ is hydrogen.44. The compound of claim 20, wherein X is N, R³ is hydrogen and R² ishydrogen.
 45. The compound of claim 44, wherein R³ is hydrogen.
 46. Thecompound of claim 44, wherein R⁶ is hydrogen.
 47. The compound of claim45, wherein R⁶ is hydrogen.
 48. The compound of claim 44, wherein Z isbonded to at least one of the carbons at the 6 or 7 position of thebicyclic ring.
 49. The compound of claim 45, wherein Z is bonded to atleast one of the carbons at the 6 or 7 position of the bicyclic ring.50. The compound of claim 46, wherein Z is bonded to at least one of thecarbons at the 6 or 7 position of the bicyclic ring.
 51. The compound ofclaim 47, wherein Z is bonded to at least one of the carbons at the 6 or7 position of the bicyclic ring.
 52. The compound of claim 48, wherein Zis bonded to the carbon at the 6 position of the bicyclic ring.
 53. Thecompound of claim 49, wherein Z is bonded to the carbon at the 6position of the bicyclic ring.
 54. The compound of claim 50, wherein Zis bonded to the carbon at the 6 position of the bicyclic ring.
 55. Thecompound of claim 51, wherein Z is bonded to the carbon at the 6position of the bicyclic ring.
 56. The compound of claim 46, wherein Vis CH₂.
 57. The compound of claim 47, wherein V is CH₂.
 58. The compoundof claim 50, wherein V is CH₂.
 59. The compound of claim 51, wherein Vis CH₂.
 60. The compound of claim 54, wherein V is CH₂.
 61. The compoundof claim 55, wherein V is CH₂.
 62. The compound of claim 56, wherein R⁹is hydrogen.
 63. The compound of claim 57, wherein R⁹ is hydrogen. 64.The compound of claim 58, wherein R⁹ is hydrogen.
 65. The compound ofclaim 59, wherein R⁹ is hydrogen.
 66. The compound of claim 60, whereinR⁹ is hydrogen.
 67. The compound of claim 61, wherein R⁹ is hydrogen.68. The compound of claim 7, wherein X is N and R³ is hydrogen.
 69. Thecompound of claim 68, wherein R³ is hydrogen.
 70. The compound of claim68, wherein R⁶ is hydrogen.
 71. The compound of claim 69, wherein R⁶ ishydrogen.
 72. The compound of claim 68, wherein Z is bonded to at leastone of the carbons at the 6 or 7 position of the bicyclic ring.
 73. Thecompound of claim 69, wherein Z is bonded to at least one of the carbonsat the 6 or 7 position of the bicyclic ring.
 74. The compound of claim70, wherein Z is bonded to at least one of the carbons at the 6 or 7position of the bicyclic ring.
 75. The compound of claim 71, wherein Zis bonded to at least one of the carbons at the 6 or 7 position of thebicyclic ring.
 76. The compound of claim 72, wherein Z is bonded to thecarbon at the 6 position of the bicyclic ring.
 77. The compound of claim73, wherein Z is bonded to the carbon at the 6 position of the bicyclicring.
 78. The compound of claim 74, wherein Z is bonded to the carbon atthe 6 position of the bicyclic ring.
 79. The compound of claim 75,wherein Z is bonded to the carbon at the 6 position of the bicyclicring.
 80. The compound of claim 70, wherein V is CH₂.
 81. The compoundof claim 71, wherein V is CH₂.
 82. The compound of claim 74, wherein Vis CH₂.
 83. The compound of claim 75, wherein V is CH₂.
 84. The compoundof claim 78, wherein V is CH₂.
 85. The compound of claim 79, wherein Vis CH₂.
 86. The compound of claim 80, wherein R⁹ is hydrogen.
 87. Thecompound of claim 81, wherein R⁹ is hydrogen.
 88. The compound of claim82, wherein R⁹ is hydrogen.
 89. The compound of claim 83, wherein R⁹ ishydrogen.
 90. The compound of claim 84, wherein R⁹ is hydrogen.
 91. Thecompound of claim 85, wherein R⁹ is hydrogen.
 92. A method of treatinghyperproliferative diseases in a mammal comprising administering atherapeutically effective amount of the compound defined in claim 20 tosaid mammal.
 93. A method of treating hyperproliferative diseases in amammal comprising administering a therapeutically effective amount ofthe compound defined in claim 28 to said mammal.
 94. A method oftreating hyperproliferative diseases in a mammal comprisingadministering a therapeutically effective amount of the compound definedin claim 32 to said mammal.
 95. A method of treating hyperproliferativediseases in a mammal comprising administering a therapeuticallyeffective amount of the compound defined in claim 44 to said mammal. 96.A method of treating hyperproliferative diseases in a mammal comprisingadministering a therapeutically effective amount of the compound definedin claim 52 to said mammal.
 97. A method of treating hyperproliferativediseases in a mammal comprising administering a therapeuticallyeffective amount of the compound defined in claim 56 to said mammal. 98.A method of treating hyperproliferative diseases in a mammal comprisingadministering a therapeutically effective amount of the compound definedin claim 68 to said mammal.
 99. A method of treating hyperproliferativediseases in a mammal comprising administering a therapeuticallyeffective amount of the compound defined in claim 76 to said mammal.100. A method of treating hyperproliferative diseases in a mammalcomprising administering a therapeutically effective amount of thecompound defined in claim 80 to said mammal.
 101. A compound accordingto claim 1 which is selected from2-methoxy-N-((4-(3-methyl-4-phenoxyphenylamino)quinazolin-6-yl)methyleneamino)acetamidine;_(—)2-Methoxy-N-methyl-N-((4-(3-methyl-4-phenoxyphenylamino)quinazolin-6-1)methyleneamino)acetamidine;N-((4-(4-(3-Fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)methyleneamino)-2-methoxyacetamidine;N-(4-(3-Methyl-4-(6-methylpyridin-3-yloxy)phenylamino)quinazolin-6-yl)methyleneamino-2-methoxyacetamidine;N-((4-(4-(3-Fluorobenzyloxy)-3-chlorophenylamino)-quinazolin-6-yl)-methyleneamino)-acetamidine;N4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-N6-(4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine;N4-[3-chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine;N4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(3,8-dioxa-1-aza-spiro[4.5]dec-1-en-2-yl)-quinazoline-4,6-diamine;N6-(3,8-Dioxa-1-aza-spiro[4.5]dec-1-en-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine;and2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydropyrrolo[3,4-d]oxazole-5-carboxylicacid tert-butyl ester.
 102. A compound according to claim 1 which isselected fromN4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine;1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydropyrrolo[3,4-d]oxazol-5-yl)-ethanone;N4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(3-oxa-1,8-diaza-spiro[4.5]dec-1-en-2-yl)-quinazoline-4,6-diamine;1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3-oxa-1,8-diazaspiro[4.5]dec-1-en-8-yl)-ethanone;N6-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine;N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(1-oxa-3,8-diazaspiro[4.5]dec-2-en-2-yl)-quinazoline-4,6-diamine;1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-1-oxa-3,8-diazaspiro[4.5]dec-2-en-8-yl)-ethanone;(4-Methyl-2-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-4,5-dihydrooxazol-4-yl)-methanol;N4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(1,8-dioxa-3-aza-spiro[4.5]dec-2-en-2-yl)-quinazoline-4,6-diamine;andN6-(1,8-Dioxa-3-azaspiro[4.5]dec-2-en-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine.103. A compound according to claim 1 which is selected fromN4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(5-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine;N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine;N6-(5,5-Dimethyl-4,5-dihydrooxazol-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine;N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine;N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine;N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(1,8-dioxa-3-aza-spiro[4.5]dec-2-en-2-yl)-quinazoline-4,6-diamine;N4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(5-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine;N4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine;(1RS,5SR)-1-(5-methyl-2-(4-(3-methyl-4-(6-methylpyridin-3-yloxy)phenylamino)quinazolin-6-ylamino)-4,5-dihydrooxazol-5-yl)ethanol;andN6-(4,5-Dihydrooxazol-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine.104. A compound according to claim 1 which is selected from(2-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-4-methyl-4,5-dihydro-oxazol-4-yl)-methanol;(1RS,5SR)-1-(2-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)quinazolin-6-ylamino)-5-methyl-4,5-dihydrooxazol-5-yl)ethanol;N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine;(1-RS,5SR)-1-(2-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-ylamino)-5-methyl-4,5-dihydrooxazol-5-yl)ethanol;N6-(5-Methyl-4,5-dihydrooxazol-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine;N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine;N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(1,8-dioxa-3-aza-spiro[4.5]dec-2-en-2-yl)-quinazoline-4,6-diamine;N6-(4-Methyl-4,5-dihydrooxazol-2-yl)-N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine;N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine;andN4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine.105. A compound according to claim 1 which is selected fromN4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine;N4-[3-Methyl-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(3a,4,6,6a-tetrahydrofuro[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine;N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(1,8-dioxa-3-aza-spiro[4.5]dec-2-en2-yl)-quinazoline-4,6-diamine;N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(5-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine;N4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(4-methyl-4,5-dihydrooxazol-2-yl)-quinazoline-4,6-diamine;N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine;N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine;(2-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-ylamino}-4-methyl-4,5-dihydro-oxazol-4-yl)-methanol;N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(6-oxa-4-aza-spiro[2.4]hept-4-en-5-yl)-quinazoline-4,6-diamine;and(2-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-4-hydroxymethyl-4,5-dihydro-oxazol-4-yl)-methanol.106. A compound according to claim 1 which is selected from(R)-1-((S)-2-(4-(3-chloro-4-(thiazol-2-ylmethoxy)phenylamino)quinazolin-6-ylamino)-4,5-dihydrooxazol-4-yl)ethanol;(R)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine;(S)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine;(S)-N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(5-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine;(R)-N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(5-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine;N4-[4-(5-Chloro-pyridin-3-yloxy)-3-methyl-phenyl]-N6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine;N6-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-N4-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-quinazoline-4,6-diamine;andN6-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-N4-[4-(5-fluoro-pyridin-3-yloxy)-3-methyl-phenyl]-quinazoline-4,6-diamine.